Olanzapine enhances the response of PD-(L)1 inhibitor immunotherapy: A retrospective efficacy analysis in advanced malignancies

Olanzapine enhances the response of PD-(L)1 inhibitor immunotherapy: A retrospective efficacy analysis in advanced malignancies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Olanzapine enhances the response of PD-(L)1 inhibitor immunotherapy: A retrospective efficacy analysis in advanced malignancies Meng-xue Mei, Yan-ling Yi, Hai-hui Wang, Jiang-zhe Ye, Zhen-jie Huang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8497529/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives This retrospective cohort study explores olanzapine’s immunomodulatory role and clinical impact in advanced cancer patients on PD-(L)1 inhibitors, given chronic stress may impair immune checkpoint inhibitor efficacy. Methods Among 1933 advanced cancer patients receiving PD-(L)1 inhibitors + chemotherapy (2018–2022), 99 received concurrent olanzapine for chemotherapy induced nausea. After excluding 58 cases, 41 olanzapine-treated patients were propensity score-matched (PSM) for age, gender, and cancer type. Survival outcomes were analyzed via Kaplan–Meier curves and log-rank tests. Results The olanzapine cohort showed higher ORR (39.02% vs. 26.83%), comparable median PFS (9 vs. 6 months, P = 0.057), and significantly longer median OS (28 vs. 9 months, P = 0.019). Multivariate analysis confirmed olanzapine correlated with prolonged OS (HR = 0.510, 95% CI:0.282–0.917, P = 0.026). Conclusions Olanzapine may enhance survival benefits in advanced cancer patients undergoing PD-(L)1 inhibitor therapy. Immunotherapy PD-(L)1 Olanzapine Advanced malignancies Survival Figures Figure 1 Figure 2 Figure 3 Introduction Immune checkpoint inhibitors (ICIs), particularly PD-(L)1 monoclonal antibodies, have emerged as the fourth cornerstone of cancer therapy alongside surgery, chemotherapy, and radiotherapy, significantly improving survival outcomes in advanced malignancies ( 1 ). However, substantial heterogeneity in treatment response persists, with efficacy modulated by complex host-intrinsic and extrinsic factors. ICIs-mediated immunotherapy has only 20%-30% of patients benefit from it ( 2 ). Emerging evidence indicates that chronic psychological stress–a critical microenvironmental variable–may impede antitumor immunity via neuroendocrine immune axis dysregulation, thereby diminishing clinical benefits from ICIs ( 3 – 5 ). Previous studies have indicated that the incidence of depression among cancer patients is increasing annually and is over five times higher than that of the general population ( 6 ). Concurrently, depression significantly reduces the quality of life and increases mortality in patients with malignant tumors ( 7 ). The STRESS-LUNG-1 prospective study demonstrated that in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors, higher levels of emotional distress are associated with a worse therapeutic response to these inhibitors ( 3 ). Furthermore, numerous studies have shown that combining immune checkpoint inhibitors with other cancer therapies enhances clinical responses and exerts synergistic effects in patients with various cancer types ( 8 ). Emerging evidence from studies suggests that antidepressants may exert beneficial effects beyond their established role in alleviating anxiety and depression in cancer patients. These agents have been shown to modulate multiple signaling pathways and influence tumor microenvironment dynamics, potentially contributing to direct anti-tumor activity and mitigation of chemotherapy-induced side effects ( 9 ). Notably, preclinical research has demonstrated that fluoxetine, through antagonism of serotonin signaling, can downregulate tumor PD-L1 expression in murine models. This immunomodulatory effect enhances the efficacy of immune checkpoint inhibitors, resulting in significantly suppressed tumor progression when used in combination with immunotherapy ( 10 ). As research advances, growing experimental and translational data support the synergistic potential of combining antidepressants with conventional anticancer treatments. Such combinations appear to enhance antitumor responses by promoting immune system activation, alleviating cancer-related symptoms, improving patients’ quality of life, and potentially extending survival-highlighting a novel, multidimensional therapeutic role for these drugs in oncology. Despite these promising insights, robust clinical evidence evaluating the impact of antidepressant use on immunotherapy outcomes in human cancer populations remains sparse. Well-designed prospective trials are therefore needed to clarify whether these observed preclinical benefits translate into tangible clinical improvements, and to identify optimal patient subgroups, timing, and specific antidepressant classes for integration into cancer immunotherapeutic strategies. Given the widespread use of antipsychotics (For example, olanzapine) for managing cancer-related symptoms such as chemotherapy-induced nausea, insomnia, and anxiety, their potential immunomodulatory properties warrant rigorous investigation. To address this gap, we conducted a retrospective cohort analysis evaluating the association between adjunctive olanzapine use and clinical outcomes in advanced cancer patients receiving PD-(L)1 inhibitor therapy. Methods Study design and participants From January 2018 to December 2022, a total of 1933 treatment-naive patients with advanced malignant tumors received PD-(L)1 inhibitor immunotherapy combined with chemotherapy at the Second Affiliated Hospital of Nanchang University, among whom 99 were concurrently treated with olanzapine to prevent chemotherapy-induced nausea. A total of 58 cases were excluded, including 2 patients treated with PD-1 monoclonal antibody combined with CTLA-4 monoclonal antibody, 11 patients with incomplete treatment records, and 45 patients lost to follow-up (Fig. 1 ). To analyze survival outcomes in patients receiving PD-(L)1 inhibitor plus olanzapine, we adjusted for age, gender, smoking history, BMI, PS (Performance Status score), and cancer type using propensity score matching (PSM). Permission to conduct the study was obtained from the Ethics Committee of the Second Affiliated Hospital of Nanchang University at the beginning of the study. Informed consent was obtained from all human subjects. The endpoints in this study were overall survival and progression-free survival. The median follow-up time in this study was 13 months (range 1–41 months). The date of last follow-up was May 10, 2025. Progression-free survival (PFS) was defined as the time from the date of PD-(L)1 inhibitors therapy initiation to the date of disease progression. The disease progression was based on radiological evaluation and/or clinical progression using the Response Evaluation Criteria in Solid Tumors criteria (RECIST) (version 1.1). Overall survival (OS) was defined as the time from the date of PD-(L)1 inhibitors therapy initiation after diagnosis as advanced malignant tumors to the date of death for any reason. Statistical analysis Descriptive statistics were used to summarize baseline patient characteristics. To eliminate the effect of confounding covariates on survival analysis, PSM was performed using one-to-one nearest neighbor matching. The Kaplan–Meier survival curves and log-rank test were used to analyze OS and PFS. Cox proportional hazards regression model was utilized to calculate the hazard ratios (HRs) and their 95% confidence intervals (CIs). P value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics software (version 26.0). Results Patient characteristics Forty-one advanced cancer patients administered olanzapine plus PD-(L)1 inhibitors were enrolled. A PSM-matched control cohort (n = 41) received first-line PD-(L)1 inhibitors without olanzapine. It can be seen that the baseline factors were not significantly different between the olanzapine combination therapy cohort and Control cohort (all P > 0.05) (Table 1 ). The median treatment time for olanzapine was 14 days (range 5–67 days) in the olanzapine combination therapy cohort. The median age was 63 years old (range 34–75 years). Table 1 Clinical characteristics of patients received olanzapine combination PD-(L)1 inhibitors therapy cohort and control cohort after PSM. Characteristic Total (n = 82) olanzapine combination therapy cohort (n = 41) control cohort (n = 41) P Value Sex, No(%) 0.800 Male 61(74.4) 31(75.6) 30(73.2) Female 21(25.6) 10(24.4) 11(26.8) Age, No(%) 0.969 70 26(31.7) 13(31.7) 13(31.7) BMI, No(%) 0.596 24 16(19.5) 8(19.5) 8(19.5) Smoker, No(%) 0.800 Yes 21(25.6)) 10(24.4) 11(26.8) No 61(74.4) 31(75.6) 30(73.2) Alcoholic, No(%) 0.577 Yes 16(19.5) 7(17.1) 9(22.0) No 66(80.5) 34(82.9) 32(78.0) PS, No(%) 1.000 0 3(3.7) 0(0.0) 3(7.3) 1 ~ 2 79(96.3) 41(100.0) 38(92.7) 3 ~ 4 0(0.0) 0(0.0) 0(0.0) Type of tumor, No(%) 0.970 Lunge cancer 35(42.7) 18(43.9) 17(41.5) Gastrointestinal cancer 16(19.5) 8(19.5) 8(19.5) Others 31(37.8) 15(36.6) 16(39.0) Survival outcomes The objective response rate (ORR) in the olanzapine combination therapy cohort and control cohort were 39.02% (16/41) vs 26.83% (11/41), respectively. The disease control rate (DCR) in the olanzapine combination therapy cohort and control cohort were 73.17% (30/41) vs 63.41% (26/41), respectively. As of the follow-up endpoint, 18 deaths were recorded in the olanzapine combination therapy group versus 30 in the control group. Regarding continuous disease remission, 14 patients in the combination therapy group achieved this outcome, compared with only 5 in the control group (Fig. 2 ). Kaplan–Meier survival curve analysis showed patients with olanzapine combination therapy have significantly longer median OS than control cohort (mOS: 28 vs. 9 months; HR: 0.495 (95%CI: 0.275 − 0.892); P = 0.019). The survival analysis showed that patients with olanzapine combination therapy have longer median PFS than control cohort (mPFS: 9 vs. 6 months; HR: 0.581 (95%CI: 0.332 − 1.017); ), but it's not statistically significant (Fig. 3 ). Multivariate analysis confirmed that olanzapine use was significantly associated with prolonged OS in patients receiving PD-(L)1 inhibitors immunotherapy (HR = 0.510, 95% CI: 0.282–0.917, P = 0.026). Discussion For many patients with advanced malignancies, factors including treatment confidence, toxic side effects, and economic pressures contribute to chronic psychological stress, often manifesting as depression and anxiety. Extensive preclinical evidence indicates that psychological states significantly influence cancer progression and the efficacy of immunotherapy. The most widely accepted mechanism posits that emotional distress impairs immune surveillance and anti-tumor immune responses through neuroendocrine pathways mediated by β-adrenergic/ glucocorticoid signaling ( 11 ). Chronic stress induces persistent dysregulation of the neuroendocrine system, leading to the sustained release of stress hormones such as glucocorticoids, epinephrine, and norepinephrine ( 12 ). These hormones activate corresponding signaling pathways, alter the tumor microenvironment (TME), and suppress the activation, infiltration, and cytotoxic function of CD8 + T cells ( 13 ). Consequently, this cascade undermines the response to PD-1 blockade therapy ( 14 ), compromises immune surveillance and inhibition, and ultimately promotes tumor initiation, progression, metastasis, and multidrug resistance-a key factor contributing to immunotherapy failure. A recent post hoc analysis of the Phase II PRADO trial investigated the association between pretreatment emotional distress (ED) and the efficacy of neoadjuvant immunotherapy in melanoma patients. The analysis revealed that compared with the no-ED group, the baseline ED group showed a lower major pathological response rate (46% vs. 65%) and reduced 2-year relapse-free survival (74% vs. 91%) ( 15 ). Furthermore, a study by Fang Wu’s team on advanced NSCLC patients also indicated a link between emotional distress and diminished response to ICIs. The study reported significantly shorter progression-free survival in the ED group and a higher risk of overall survival events, supporting that psychological stress is associated with poorer efficacy of ICIs in advanced NSCLC. These studies and findings suggest a potential link between psychological status and the efficacy of immunotherapy. In recent years, a growing body of preclinical research has explored the effects of antidepressant drugs on cancer. One study demonstrated that sertraline could sensitize human lung cancer cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL, a potential target in cancer therapy) and may also serve as a treatment option for cancer patients with depression ( 16 ). Another study reported that fluoxetine, by antagonizing serotonin in mice, altered the tumor microenvironment, leading to decreased PD-L1 expression in tumors, slowed tumor growth, and, when combined with immunotherapy, induced prolonged arrest of cancer progression ( 10 ). However, clinical evidence regarding the association between antidepressant use and immunotherapy outcomes remains limited. In this study, we observed that patients receiving olanzapine in combination with ICIs exhibited a significantly longer median OS compared to those in the control cohort. Additionally, the combination group demonstrated a higher ORR, suggesting that olanzapine may enhance the therapeutic efficacy of ICIs in patients with advanced tumors. These findings further support the hypothesis that targeting ED could modulate the tumor immune microenvironment and potentially improve ICI outcomes, implicating patients’ psychological status as a potential predictive biomarker for immunotherapy response. Despite these promising results, several limitations warrant consideration. First, the retrospective and non-randomized design of the study inherently carries a risk of selection bias. Second, our cohort encompassed multiple tumor types rather than being restricted to a single cancer lineage. While this broad inclusion enhances generalizability, it also introduces heterogeneity due to variations in tumor biology and inherent responsiveness to immunotherapy across different malignancies. Therefore, future large-scale, prospective, and ideally randomized studies are needed to validate these findings and elucidate the underlying mechanisms by which psychotropic interventions like olanzapine may synergize with ICIs. Abbreviations CI: confidence interval DCR: disease control rate ED: emotional distress HR: hazard ratio ICI: immune checkpoint inhibitor NSCLC: non-small cell lung cancer ORR: objective response rate OS: overall survival PFS: progression-free survival PSM: propensity score-matched RECIST: Response Evaluation Criteria in Solid Tumors TME: tumor microenvironment Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. The study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Informed consent was obtained from all participants and/or their legal guardian(s). Consent for publication Not Applicable Availability of data and materials All data generated or analysed during this study are included in this published article [Table. S1]. Competing Interests The authors declare that they have no competing interests. Funding This work was supported by the Wu Jieping Foundation of China [grant number: 320.6750.2025-06-233]. These funding bodies had no role in the design of the study, no role in the collection, analysis, and interpretation of data and no role in writing the manuscript. Authors' contributions Meng-xue Mei, Hai-hui Wang, Jiang-zhe Ye and Sha Zhao collected patient data. Yan-ling Yi and long huang wrote the main manuscript text. Zhen-jie Huang and An-wen Liu prepared figures 1-3. All authors reviewed the manuscript. Acknowledgement The authors are grateful to all the patients and their families involved in the study. References Velcheti V, Rai P, Kao YH, et al. 5-Year Real-World Outcomes With Frontline Pembrolizumab Monotherapy in PD-L1 Expression ≥ 50% Advanced NSCLC. Clin Lung Cancer. 2024;25(6):502–e5083. Rui R, Zhou L, He S. Cancer immunotherapies: advances and bottlenecks. Front Immunol. 2023;14. Zeng Y, Hu CH, Li YZ, et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med. 2024;30(6):1680–8. Bai Cui F, Peng J, Lu et al. Cancer and stress: NextGen strategies.Brain Behav Immun. 2021 Mar:93:368–83. Qidong Zhou Z, Qian W, Ding, et al. Chronic Psychological Stress Attenuates the Efficacy of anti-PD-L1 Immunotherapy for Bladder Cancer in Immunocompetent Mice. Cancer Invest. 2021 Jul-Aug;39(6–7):571–81. Hartung TJ, Brähler E, Faller H, et al. The risk of being depressed is significantly higher in cancer patients than in the general population: Prevalence and severity of depressive symptoms across major cancer types. Eur J Cancer. 2017;72:46–53. McCarty S, Eickmeyer SM, Kocherginsky M, et al. Health-Related Quality of Life and Cancer-Related Symptoms During Interdisciplinary Outpatient Rehabilitation for Malignant Brain Tumor. Am J Phys Med Rehabil. 2017;96(12):852–60. Salama AKS, Moschos SJ. Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies. Ann Oncol. 2017;28(1):57–74. Zheng Y, Chang X, Huang Y, He D. The application of antidepressant drugs in cancer treatment. Biomed Pharmacother. 2023;157:113985. Schneider MA, Heeb L, Beffinger MM, et al. Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models. Sci Transl Med. 2021;13:611. Tian W, Liu Y, Cao C et al. Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments. Front Cell Dev Biol. 2021;9. Eckerling A, Ricon-Becker I, Sorski L, et al. Stress and cancer: mechanisms, significance and future directions. Nat Rev Cancer. 2021;21(12):767–85. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71. Bucsek MJ, Qiao G, MacDonald CR, et al. β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8 + T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Res. 2017;77(20):5639–51. Fraterman I, Reijers ILM, Dimitriadis P, et al. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. Nat Med. 2023;29(12):3090–9. Zinnah K, Seol J, Park S. Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int J Mol Med. 2020;46(2):795–805. Additional Declarations No competing interests reported. Supplementary Files Table.S1.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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15:49:55","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65568,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8497529/v1/cbd883d0314696e0b5e78573.html"},{"id":100546684,"identity":"80afbcbc-a0c4-40f2-9629-f9a1bcc5b631","added_by":"auto","created_at":"2026-01-19 08:11:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":424160,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8497529/v1/57ce4af733a9713e8ca76585.png"},{"id":100436955,"identity":"69fd2998-8382-4c88-b35e-e2780fb1e4f3","added_by":"auto","created_at":"2026-01-16 15:49:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":343629,"visible":true,"origin":"","legend":"\u003cp\u003eSwimming plot illustrating treatment history of patients.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8497529/v1/536766de5f0628e211e47b6f.png"},{"id":100547453,"identity":"76b6019a-415c-480e-aa21-84911cf929b0","added_by":"auto","created_at":"2026-01-19 08:15:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":338362,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve and subgroup analysis of PFS and OS. P values were calculated using a two-sided log-rank test. The HR and the corresponding 95% CI were calculated using a Cox proportional-hazards.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8497529/v1/ac252b2116e3c4da185edccb.png"},{"id":101298151,"identity":"9e663d23-622a-44da-8c3f-e4c16f571baa","added_by":"auto","created_at":"2026-01-28 09:31:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1741410,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8497529/v1/e151a15d-b5cb-4ae1-b02a-47b98954931e.pdf"},{"id":100547382,"identity":"f00a5a0f-6c7f-464f-af13-7ceec9f47d75","added_by":"auto","created_at":"2026-01-19 08:15:23","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":16933,"visible":true,"origin":"","legend":"","description":"","filename":"Table.S1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8497529/v1/aa9a6d8356963a9451842593.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Olanzapine enhances the response of PD-(L)1 inhibitor immunotherapy: A retrospective efficacy analysis in advanced malignancies","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors (ICIs), particularly PD-(L)1 monoclonal antibodies, have emerged as the fourth cornerstone of cancer therapy alongside surgery, chemotherapy, and radiotherapy, significantly improving survival outcomes in advanced malignancies (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). However, substantial heterogeneity in treatment response persists, with efficacy modulated by complex host-intrinsic and extrinsic factors. ICIs-mediated immunotherapy has only 20%-30% of patients benefit from it (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEmerging evidence indicates that chronic psychological stress\u0026ndash;a critical microenvironmental variable\u0026ndash;may impede antitumor immunity via neuroendocrine immune axis dysregulation, thereby diminishing clinical benefits from ICIs (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Previous studies have indicated that the incidence of depression among cancer patients is increasing annually and is over five times higher than that of the general population (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Concurrently, depression significantly reduces the quality of life and increases mortality in patients with malignant tumors (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The STRESS-LUNG-1 prospective study demonstrated that in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors, higher levels of emotional distress are associated with a worse therapeutic response to these inhibitors (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Furthermore, numerous studies have shown that combining immune checkpoint inhibitors with other cancer therapies enhances clinical responses and exerts synergistic effects in patients with various cancer types (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEmerging evidence from studies suggests that antidepressants may exert beneficial effects beyond their established role in alleviating anxiety and depression in cancer patients. These agents have been shown to modulate multiple signaling pathways and influence tumor microenvironment dynamics, potentially contributing to direct anti-tumor activity and mitigation of chemotherapy-induced side effects (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Notably, preclinical research has demonstrated that fluoxetine, through antagonism of serotonin signaling, can downregulate tumor PD-L1 expression in murine models. This immunomodulatory effect enhances the efficacy of immune checkpoint inhibitors, resulting in significantly suppressed tumor progression when used in combination with immunotherapy (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). As research advances, growing experimental and translational data support the synergistic potential of combining antidepressants with conventional anticancer treatments. Such combinations appear to enhance antitumor responses by promoting immune system activation, alleviating cancer-related symptoms, improving patients\u0026rsquo; quality of life, and potentially extending survival-highlighting a novel, multidimensional therapeutic role for these drugs in oncology. Despite these promising insights, robust clinical evidence evaluating the impact of antidepressant use on immunotherapy outcomes in human cancer populations remains sparse. Well-designed prospective trials are therefore needed to clarify whether these observed preclinical benefits translate into tangible clinical improvements, and to identify optimal patient subgroups, timing, and specific antidepressant classes for integration into cancer immunotherapeutic strategies.\u003c/p\u003e \u003cp\u003eGiven the widespread use of antipsychotics (For example, olanzapine) for managing cancer-related symptoms such as chemotherapy-induced nausea, insomnia, and anxiety, their potential immunomodulatory properties warrant rigorous investigation. To address this gap, we conducted a retrospective cohort analysis evaluating the association between adjunctive olanzapine use and clinical outcomes in advanced cancer patients receiving PD-(L)1 inhibitor therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eFrom January 2018 to December 2022, a total of 1933 treatment-naive patients with advanced malignant tumors received PD-(L)1 inhibitor immunotherapy combined with chemotherapy at the Second Affiliated Hospital of Nanchang University, among whom 99 were concurrently treated with olanzapine to prevent chemotherapy-induced nausea. A total of 58 cases were excluded, including 2 patients treated with PD-1 monoclonal antibody combined with CTLA-4 monoclonal antibody, 11 patients with incomplete treatment records, and 45 patients lost to follow-up (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). To analyze survival outcomes in patients receiving PD-(L)1 inhibitor plus olanzapine, we adjusted for age, gender, smoking history, BMI, PS (Performance Status score), and cancer type using propensity score matching (PSM). Permission to conduct the study was obtained from the Ethics Committee of the Second Affiliated Hospital of Nanchang University at the beginning of the study. Informed consent was obtained from all human subjects.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe endpoints in this study were overall survival and progression-free survival. The median follow-up time in this study was 13 months (range 1\u0026ndash;41 months). The date of last follow-up was May 10, 2025. Progression-free survival (PFS) was defined as the time from the date of PD-(L)1 inhibitors therapy initiation to the date of disease progression. The disease progression was based on radiological evaluation and/or clinical progression using the Response Evaluation Criteria in Solid Tumors criteria (RECIST) (version 1.1). Overall survival (OS) was defined as the time from the date of PD-(L)1 inhibitors therapy initiation after diagnosis as advanced malignant tumors to the date of death for any reason.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to summarize baseline patient characteristics. To eliminate the effect of confounding covariates on survival analysis, PSM was performed using one-to-one nearest neighbor matching. The Kaplan\u0026ndash;Meier survival curves and log-rank test were used to analyze OS and PFS. Cox proportional hazards regression model was utilized to calculate the hazard ratios (HRs) and their 95% confidence intervals (CIs). P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics software (version 26.0).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eForty-one advanced cancer patients administered olanzapine plus PD-(L)1 inhibitors were enrolled. A PSM-matched control cohort (n\u0026thinsp;=\u0026thinsp;41) received first-line PD-(L)1 inhibitors without olanzapine. It can be seen that the baseline factors were not significantly different between the olanzapine combination therapy cohort and Control cohort (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median treatment time for olanzapine was 14 days (range 5\u0026ndash;67 days) in the olanzapine combination therapy cohort. The median age was 63 years old (range 34\u0026ndash;75 years).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics of patients received olanzapine combination PD-(L)1 inhibitors therapy cohort and control cohort after PSM.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;82)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eolanzapine combination therapy cohort (n\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003econtrol cohort (n\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex, No(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.800\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61(74.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31(75.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30(73.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21(25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(24.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11(26.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, No(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.969\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11(13.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6(14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5(12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45(54.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22(53.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23(56.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26(31.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13(31.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13(31.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI, No(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.596\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61(74.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30(73.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31(75.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoker, No(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.800\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21(25.6))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(24.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11(26.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61(74.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31(75.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30(73.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlcoholic, No(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.577\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7(17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9(22.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66(80.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34(82.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32(78.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePS, No(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3(7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026thinsp;~\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79(96.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41(100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38(92.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of tumor, No(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.970\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLunge cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35(42.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18(43.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17(41.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31(37.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15(36.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16(39.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival outcomes\u003c/h3\u003e\n\u003cp\u003eThe objective response rate (ORR) in the olanzapine combination therapy cohort and control cohort were 39.02% (16/41) vs 26.83% (11/41), respectively. The disease control rate (DCR) in the olanzapine combination therapy cohort and control cohort were 73.17% (30/41) vs 63.41% (26/41), respectively. As of the follow-up endpoint, 18 deaths were recorded in the olanzapine combination therapy group versus 30 in the control group. Regarding continuous disease remission, 14 patients in the combination therapy group achieved this outcome, compared with only 5 in the control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Kaplan\u0026ndash;Meier survival curve analysis showed patients with olanzapine combination therapy have significantly longer median OS than control cohort (mOS: 28 vs. 9 months; HR: 0.495 (95%CI: 0.275\u0026thinsp;\u0026minus;\u0026thinsp;0.892); P\u0026thinsp;=\u0026thinsp;0.019). The survival analysis showed that patients with olanzapine combination therapy have longer median PFS than control cohort (mPFS: 9 vs. 6 months; HR: 0.581 (95%CI: 0.332\u0026thinsp;\u0026minus;\u0026thinsp;1.017); ), but it's not statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Multivariate analysis confirmed that olanzapine use was significantly associated with prolonged OS in patients receiving PD-(L)1 inhibitors immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.510, 95% CI: 0.282\u0026ndash;0.917, P\u0026thinsp;=\u0026thinsp;0.026).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFor many patients with advanced malignancies, factors including treatment confidence, toxic side effects, and economic pressures contribute to chronic psychological stress, often manifesting as depression and anxiety. Extensive preclinical evidence indicates that psychological states significantly influence cancer progression and the efficacy of immunotherapy. The most widely accepted mechanism posits that emotional distress impairs immune surveillance and anti-tumor immune responses through neuroendocrine pathways mediated by β-adrenergic/ glucocorticoid signaling (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Chronic stress induces persistent dysregulation of the neuroendocrine system, leading to the sustained release of stress hormones such as glucocorticoids, epinephrine, and norepinephrine (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). These hormones activate corresponding signaling pathways, alter the tumor microenvironment (TME), and suppress the activation, infiltration, and cytotoxic function of CD8\u003csup\u003e+\u003c/sup\u003e T cells (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Consequently, this cascade undermines the response to PD-1 blockade therapy (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), compromises immune surveillance and inhibition, and ultimately promotes tumor initiation, progression, metastasis, and multidrug resistance-a key factor contributing to immunotherapy failure.\u003c/p\u003e \u003cp\u003eA recent post hoc analysis of the Phase II PRADO trial investigated the association between pretreatment emotional distress (ED) and the efficacy of neoadjuvant immunotherapy in melanoma patients. The analysis revealed that compared with the no-ED group, the baseline ED group showed a lower major pathological response rate (46% vs. 65%) and reduced 2-year relapse-free survival (74% vs. 91%) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Furthermore, a study by Fang Wu\u0026rsquo;s team on advanced NSCLC patients also indicated a link between emotional distress and diminished response to ICIs. The study reported significantly shorter progression-free survival in the ED group and a higher risk of overall survival events, supporting that psychological stress is associated with poorer efficacy of ICIs in advanced NSCLC.\u003c/p\u003e \u003cp\u003eThese studies and findings suggest a potential link between psychological status and the efficacy of immunotherapy. In recent years, a growing body of preclinical research has explored the effects of antidepressant drugs on cancer. One study demonstrated that sertraline could sensitize human lung cancer cells to tumor necrosis factor\u0026ndash;related apoptosis-inducing ligand (TRAIL, a potential target in cancer therapy) and may also serve as a treatment option for cancer patients with depression (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Another study reported that fluoxetine, by antagonizing serotonin in mice, altered the tumor microenvironment, leading to decreased PD-L1 expression in tumors, slowed tumor growth, and, when combined with immunotherapy, induced prolonged arrest of cancer progression (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, clinical evidence regarding the association between antidepressant use and immunotherapy outcomes remains limited.\u003c/p\u003e \u003cp\u003eIn this study, we observed that patients receiving olanzapine in combination with ICIs exhibited a significantly longer median OS compared to those in the control cohort. Additionally, the combination group demonstrated a higher ORR, suggesting that olanzapine may enhance the therapeutic efficacy of ICIs in patients with advanced tumors. These findings further support the hypothesis that targeting ED could modulate the tumor immune microenvironment and potentially improve ICI outcomes, implicating patients\u0026rsquo; psychological status as a potential predictive biomarker for immunotherapy response.\u003c/p\u003e \u003cp\u003eDespite these promising results, several limitations warrant consideration. First, the retrospective and non-randomized design of the study inherently carries a risk of selection bias. Second, our cohort encompassed multiple tumor types rather than being restricted to a single cancer lineage. While this broad inclusion enhances generalizability, it also introduces heterogeneity due to variations in tumor biology and inherent responsiveness to immunotherapy across different malignancies. Therefore, future large-scale, prospective, and ideally randomized studies are needed to validate these findings and elucidate the underlying mechanisms by which psychotropic interventions like olanzapine may synergize with ICIs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eCI:\u0026nbsp;\u003c/strong\u003econfidence interval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDCR:\u0026nbsp;\u003c/strong\u003edisease control rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eED:\u003c/strong\u003e emotional distress\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHR:\u003c/strong\u003e hazard ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eICI:\u003c/strong\u003e immune checkpoint inhibitor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNSCLC:\u003c/strong\u003e non-small cell lung cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORR:\u0026nbsp;\u003c/strong\u003eobjective response rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOS:\u003c/strong\u003e overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePFS:\u003c/strong\u003e progression-free survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePSM:\u0026nbsp;\u003c/strong\u003epropensity score-matched\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRECIST:\u003c/strong\u003e Response Evaluation Criteria in Solid Tumors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTME:\u0026nbsp;\u003c/strong\u003etumor microenvironment\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. The study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Informed consent was obtained from all participants and/or their legal guardian(s).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article [Table. S1].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Wu Jieping Foundation of China [grant number: 320.6750.2025-06-233]. These funding bodies had no role in the design of the study, no role in the collection, analysis, and interpretation of data and no role in writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeng-xue Mei, Hai-hui Wang, Jiang-zhe Ye and Sha Zhao collected patient data. Yan-ling Yi and long huang wrote the main manuscript text. Zhen-jie Huang and An-wen Liu prepared figures 1-3. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to all the patients and their families involved in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVelcheti V, Rai P, Kao YH, et al. 5-Year Real-World Outcomes With Frontline Pembrolizumab Monotherapy in PD-L1 Expression\u0026thinsp;\u0026ge;\u0026thinsp;50% Advanced NSCLC. Clin Lung Cancer. 2024;25(6):502\u0026ndash;e5083.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRui R, Zhou L, He S. Cancer immunotherapies: advances and bottlenecks. Front Immunol. 2023;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeng Y, Hu CH, Li YZ, et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med. 2024;30(6):1680\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBai Cui F, Peng J, Lu et al. Cancer and stress: NextGen strategies.Brain Behav Immun. 2021 Mar:93:368\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQidong Zhou Z, Qian W, Ding, et al. Chronic Psychological Stress Attenuates the Efficacy of anti-PD-L1 Immunotherapy for Bladder Cancer in Immunocompetent Mice. Cancer Invest. 2021 Jul-Aug;39(6\u0026ndash;7):571\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHartung TJ, Br\u0026auml;hler E, Faller H, et al. The risk of being depressed is significantly higher in cancer patients than in the general population: Prevalence and severity of depressive symptoms across major cancer types. Eur J Cancer. 2017;72:46\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCarty S, Eickmeyer SM, Kocherginsky M, et al. Health-Related Quality of Life and Cancer-Related Symptoms During Interdisciplinary Outpatient Rehabilitation for Malignant Brain Tumor. Am J Phys Med Rehabil. 2017;96(12):852\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalama AKS, Moschos SJ. Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies. Ann Oncol. 2017;28(1):57\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng Y, Chang X, Huang Y, He D. The application of antidepressant drugs in cancer treatment. Biomed Pharmacother. 2023;157:113985.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchneider MA, Heeb L, Beffinger MM, et al. Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models. Sci Transl Med. 2021;13:611.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTian W, Liu Y, Cao C et al. Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments. Front Cell Dev Biol. 2021;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEckerling A, Ricon-Becker I, Sorski L, et al. Stress and cancer: mechanisms, significance and future directions. Nat Rev Cancer. 2021;21(12):767\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBucsek MJ, Qiao G, MacDonald CR, et al. β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8\u0026thinsp;+\u0026thinsp;T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Res. 2017;77(20):5639\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFraterman I, Reijers ILM, Dimitriadis P, et al. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. Nat Med. 2023;29(12):3090\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZinnah K, Seol J, Park S. Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int J Mol Med. 2020;46(2):795\u0026ndash;805.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immunotherapy, PD-(L)1, Olanzapine, Advanced malignancies, Survival","lastPublishedDoi":"10.21203/rs.3.rs-8497529/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8497529/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study explores olanzapine\u0026rsquo;s immunomodulatory role and clinical impact in advanced cancer patients on PD-(L)1 inhibitors, given chronic stress may impair immune checkpoint inhibitor efficacy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAmong 1933 advanced cancer patients receiving PD-(L)1 inhibitors\u0026thinsp;+\u0026thinsp;chemotherapy (2018\u0026ndash;2022), 99 received concurrent olanzapine for chemotherapy induced nausea. After excluding 58 cases, 41 olanzapine-treated patients were propensity score-matched (PSM) for age, gender, and cancer type. Survival outcomes were analyzed via Kaplan\u0026ndash;Meier curves and log-rank tests.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe olanzapine cohort showed higher ORR (39.02% vs. 26.83%), comparable median PFS (9 vs. 6 months, P\u0026thinsp;=\u0026thinsp;0.057), and significantly longer median OS (28 vs. 9 months, P\u0026thinsp;=\u0026thinsp;0.019). Multivariate analysis confirmed olanzapine correlated with prolonged OS (HR\u0026thinsp;=\u0026thinsp;0.510, 95% CI:0.282\u0026ndash;0.917, P\u0026thinsp;=\u0026thinsp;0.026).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOlanzapine may enhance survival benefits in advanced cancer patients undergoing PD-(L)1 inhibitor therapy.\u003c/p\u003e","manuscriptTitle":"Olanzapine enhances the response of PD-(L)1 inhibitor immunotherapy: A retrospective efficacy analysis in advanced malignancies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-16 15:49:50","doi":"10.21203/rs.3.rs-8497529/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"12e64d82-ad8d-48ef-b35b-efda18ba98ec","owner":[],"postedDate":"January 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-28T06:57:07+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-16 15:49:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8497529","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8497529","identity":"rs-8497529","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}