Immune evasion in ovarian cancer: implications for immunotherapy and emerging treatments.

NK cells are immune cells that detect and destroy cancerous cells without prior sensitization. Several studies have shown important roles for NK cells in OC [ 51 – 53 ]. An interesting example of NK cells restraining metastatic OC was recently documented in the context of iron chelation. Previous studies showed that tumor biopsies from HGSOC exhibit increased expression of the transferrin receptor, which functions as an iron importer [ 52 ]. These tumor samples also display decreased amounts of the iron efflux pump ferroportin compared to normal ovarian tissue or low-grade serous ovarian cancers [ 52 ]. Based on these findings, a study investigated the functional role of iron availability on OC growth and the potential of intracellular iron chelator deferiprone as a therapeutic strategy for OC treatment [ 52 ]. The study demonstrated that deferiprone treatment suppressed mitochondrial respiration in ID8- Defb29/Vegfa OC cells while also facilitating the nuclear DNA damage response in these cells. ID8- Defb29/Vegfa cells are derived by expressing β-defensin 29 and ascular endothelial growth factor A (VEGF-A) in the mouse ID8 OC cell line [ 54 , 55 ]. This DNA damage response stimulated the innate immune response, particularly through type-I IFN signaling and NK cells because antibody-based NK cell depletion reversed the effect. A response of increased numbers of NK cells attenuated disease progression and boosted the effectiveness of first-line chemotherapy, as evidenced from potent ovarian tumor suppression in mice [ 52 ]. Moreover, depletion of intra-tumoral DCs (tDCs) in Itgax -DTR-GFP mice using diptheria toxin or blockade of IL-15 signaling with a blocking antibody against CD122 (the beta subunit of the IL-2/IL-15 receptor) reversed the protective NK cell accumulation at tumor locations following deferiprone treatment; this suggested that tDCs and IL-15 were important for immune mediated ovarian tumor suppression by NK cells [ 52 ]. The results further suggested that because deferiprone enhanced the innate immune response, the agent might be tested in treating OC. In addition, it might also serve as an NK cell sensitizing drug because of its ability to elicit NK cell-mediated OC control [ 52 ].

T cells play dual roles in tumor immunity, with distinct T-cell subtypes influencing outcomes [ 17 – 24 ]. These include cytotoxic CD8 + T cells that directly eradicate tumor cells, while helper CD4 + T cells support immune responses [ 17 , 18 ]. In contrast, regulatory T cells (Tregs) promote tumor progression by suppressing anti-tumor activity [ 25 ]. This occurs, in part, through immunosuppressive cytokine-mediated inhibition of CD8 + T cells and CTLA-4-driven downregulation of CD80/CD86 on DCs, which prevents CD8 + T cell activation, among other mechanisms [ 25 ]. Subsets such as Th17 cells exhibit context-dependent effects in cancer, functioning as either tumor-promoting or tumor-suppressing agents depending on the surrounding microenvironment and immune signals [ 26 ]. On the one hand, Th17 cells can support tumor growth by secreting pro-inflammatory cytokines, such as IL-17, which recruit neutrophils and enhance angiogenesis, creating a favorable niche for tumor progression [ 27 ]. On the other hand, they can suppress tumor development by boosting antitumor immunity through the activation of CD8 + T cells and the stimulation of other immune effector mechanisms [ 28 ]. The interaction between CD8 + T cells and checkpoint molecules, particularly PD-L1 and PD-L2 also directly influences OC progression and therapy response [ 29 – 31 ]. While both are B7 family members, PD-L2 has a more restricted expression pattern and higher affinity for PD-1 than PD-L1 [ 32 ]. These molecules, expressed on cancer and some immune cells, bind to PD-1 on CD8 + T cells, suppressing their activity and promoting an immunosuppressive tumor environment [ 32 ]. High PD-L2 expression is linked to poor prognosis and resistance to PD-1/PD-L1 therapies, highlighting the need to inhibit both checkpoints for lasting therapeutic benefits in OC [ 29 , 33 ]. Combination therapies that target PD-1/PD-L1 alongside other suppressive pathways or enhance the activity of tissue-resident memory T cells (TRMs) might offer other promising strategies for overcoming immune resistance in OC. Consistent with this likelihood, a previous study explored the role of TRM cells in OC, demonstrating that effective immune responses were driven by a small subset of CD8 + TRM T cells [ 34 ]. These TRM cells exhibited stem-like properties (TRMstem) that enabled continuous replenishment of effector T cells, which progressively differentiated and eventually became ‘exhausted’ and dysfunctional. These findings highlight the concept that tumor-reactive TRM cells are clonally enriched, associated with superior anti-tumor activity, and their presence can help predict better patient outcomes. This study suggests that enhancing TRM cell responses could potentially transform treatment outcomes for OC and perhaps other similar tumors that harbor a low-mutation-burden. Immune responses in HGSOCs are highly heterogeneous, influenced by metastatic spread and tumor location. A study showed that immune responses and mutational processes differ between adnexal and distant peritoneal tumors, indicating location-specific immune evasion mechanisms [ 35 ]. Using genomic and transcriptomic analyses, the study identified genotypic subtypes—HRD-Dup ( BRCA1 -associated tandem duplication), HRD-Del ( BRCA2 -associated interstitial deletions), and FBI ( CCNE1 amplification-associated foldback inversion)—each with distinct immune profiles [ 35 ]. Site-specific pathway enrichment included genes in the JAK-STAT, NF-κB, TNF-α, and TGF-β pathways, with TGF-β signaling being prominent in non-adnexal FBI tumors compared to HRD-Dup and HRD-Del. Immune cell composition also varied, with FBI tumors being enriched in naïve/memory T cells and homologous recombination deficient (HRD) tumors showing dysfunctional T cells. Immune evasion via HLA presentation loss, due to chromosome arm 6p loss of heterozygosity ( LOH) was noted, with clonal and sub-clonal patterns differing by subtype [ 35 ]. Overall, these findings demonstrate significant heterogeneity in immune composition and evasion, posing challenges for effective immunotherapy and emphasizing the need for site-specific treatment strategies in HGSOC.

Beyond adaptive immunity, innate immune cells such as NK cells, macrophages, DCs, and neutrophils are also important players in ovarian tumor growth and progression [ 39 , 46 – 50 ]. Below, we describe some of the known roles of these cells in cancer immune regulation, with an emphasis on OC ( Figure 2 ).

Cancer vaccines have also gained attention as a strategy to stimulate the immune system against cancer ( Key Figure Figure 3 ). Sipuleucel-T, the first US FDA-approved cancer vaccine, demonstrated 22% reduction in risk of death and increased median survival by over four months in prostate cancer patients [ 91 ]. Another notable vaccine, V940/mRNA-4157, is a personalized mRNA-based vaccine encoding up to 34 patient-specific tumor neoantigens. This vaccine has shown promise in high-risk melanoma and is being expanded for non-small cell lung cancer trials, offering hope for similar strategies in OC; specifically, it has been documented to enhance recurrence-free survival when used in conjunction with pembrolizumab relative to pembrolizumab monotherapy [ 92 ]. In addition, several studies highlight the potential of DC-based vaccines for OC treatment [ 93 – 95 ]. A DC-based vaccine targeting folate receptor alpha (FRα) was tested in a phase I trial involving stage IIIC-IV OC patients in first remission ( NCT02111941 ) viii [ 93 ]. Intradermal injections of antigen-loaded DCs induced Th1, Th17, and antibody responses, with Th1 and antibody responses correlating with longer recurrence-free survival. At a median follow-up of 49.2 months, 39% (7/18) of patients remained recurrence-free. No grade 3 or higher adverse events occurred. Further studies with larger patient cohorts and extended follow-up periods are needed to provide a clearer understanding of its potential as a standalone therapy. Similarly, a phase II trial investigating autologous DC immunotherapy (DCVAC) found a 61% reduction in progression risk and significantly improved PFS when combined with chemotherapy, compared to chemotherapy alone in OC patients NCT02107937 ix , EudraCT2010–021462-30 x [ 95 ]. Although OS in OC patients improved, it did not reach statistical significance (p=0.0557). A follow-up study showed that patients with low tumor mutational burden (TMB) and low CD8 + T cell infiltration responded better to DCVAC than those with high TMB and abundant CD8 + T cells, who fared better with standard chemotherapy [ 94 ]. These findings suggest that DCVAC might benefit OC patients with low TMB and limited T cell infiltration, pending further rigorous testing.

The mammalian immune system plays a central role in suppressing tumor initiation and progression, and consists of adaptive and innate immune systems [ 6 , 7 ]. These contribute uniquely to either detecting and destroying cancer cells or enabling tumor progression [ 7 ]. Cancer cells survive the cytotoxic effects of both adaptive and innate immune systems - a process called immune evasion [ 8 , 9 ].

B-cell subtypes can exhibit anti-tumor or pro-tumorigenic roles depending on their function and context[ 36 , 37 ]. Regulatory B cells (Bregs) often promote tumor growth by suppressing immune responses, while plasma cells and memory B cells contribute to anti-tumor immunity through antibody production and immune activation [ 36 , 37 ]. The balance between these subtypes influences tumor progression and therapy outcomes. Recent studies also show that tumor-infiltrating B cells and plasma cells (collectively referred to as TIL-Bs) are an important determinant of anti-tumor immune responses and cancer-specific prognosis in some cases [ 38 ]. Most tumors that are immunologically responsive harbor TIL-Bs in addition to T cells, indicating active and complementary immunological engagement against cancer cells [ 39 – 42 ]. As mentioned, B cells can also been play a key role in tumor regulation [ 41 , 42 ]. A study showed that CD20 + tumor-infiltrating B cells, which exhibited class-switch recombination, somatic hypermutation, and oligoclonality, could help predict improved survival in HGSOC patients, especially when combined with an analysis of tumor-infiltrating CD8 + T cells [ 42 ]. Additionally, tumor-infiltrating plasma cells were associated with tertiary lymphoid structures (TLS), cytotoxic T-cell responses, and better prognosis in OC [ 41 ]. TLSs, which mimic secondary lymphoid organs, facilitate coordinated anti-tumor responses involving both cytotoxic T cells and antibody-producing plasma cells [ 43 ]. However, it is important to note that TLS heterogeneity can affect anti-tumor immunity, and thus needs to be considered when evaluating immunotherapy outcomes [ 44 , 45 ]. Another study evaluated the nature and functional relevance of memory B cells and plasma cells in OC [ 39 ]. This study demonstrated that tumor antigen-specific and antigen-independent IgA responses suppressed OC growth through coordinated T and B-cell responses. In particular, antigen-independent IgA responses occured via non-specific transcytosis through polymeric immunoglobin receptor (pIgR + ) cancer cells. The authors also observed that myeloid cells, such as DCs and macrophages were necessary for IgA-mediated OC suppression. This study highlights the importance of developing immunotherapies that can stimulate coordinated T- and B-cell responses against OC, a setting in which immunotherapies engaging only T-cell responses have to date not yielded desired clinical outcomes. Additionally, similar to T cells, B cells can also exert pro-tumorigenic effects. Bregs, which are a B cell subset producing interleukin 10 (IL-10), can suppress the proliferation of cytotoxic T cells, DCs, and NK cells while supporting the proliferation of Tregs [ 37 ]. Bregs can also suppress anti-tumor immunity against OC cells in part via IL-10 and by suppressing IFN-γ production from CD8 + T cells [ 37 ]. These studies underscore the complex role of B-cells and their interactions with other immune cells in influencing anti-tumor or pro-tumor immune responses.

Ovarian cancer (OC) is the most lethal gynecologic malignancy and one of the leading causes of cancer-related deaths in women [ 1 , 2 ]. While a small proportion of OC cases can be attributed to genetic mutations, such as those in BRCA1 or BRCA2 , the majority of OC cases are sporadic. Several factors influence the risk of OC, including age, exposure to oral contraceptives, endometriosis, infertility, and polycystic ovarian syndrome [ 2 , 3 ]. OC is a heterogeneous disease with several histological subtypes, each with distinct pathological and clinical features [ 4 ]. High-grade serous ovarian cancer (HGSOC) is one of the most aggressive subtypes of epithelial OC and is the most common subtype, accounting for approximately 70–80% of all epithelial OC cases [ 5 ]. The immune system plays a central role in suppressing tumor initiation and progression, and consists of the adaptive and innate branches [ 6 , 7 ]. The adaptive immune system includes lymphocytes, such as B and T cells, each with distinct roles in either suppressing or promoting cancer in a context-dependent manner[ 6 ]. The innate immune system provides the first line of defense against cancer through rapid and non-specific responses, involving various cells such as neutrophils, macrophages, dendritic cells (DC) and natural killer (NK) cells. These contribute uniquely to either detecting and destroying cancer cells or enabling tumor progression [ 7 ]. Cancer cells can survive the cytotoxic effects of both adaptive and innate immune responses, a process called immune evasion [ 8 , 9 ]. The current treatment of OC is guided by the stage of the disease and patient performance status [ 1 , 10 , 11 ]. Primary treatment for advanced disease typically includes surgery and platinum-based chemotherapy (either adjuvant or neoadjuvant) followed by maintenance therapies, such as PARP inhibitors or bevacizumab, in select populations. Recurrent disease can be more challenging to treat and may involve a combination of chemotherapy, targeted agents such as bevacizumab, and surgery in certain cases. Recently, immunotherapies have been explored in recurrent OC; however, due to either intrinsic or acquired resistance, the benefits of immunotherapies have been limited. A deeper understanding of the factors that drive responses in OC may allow for the effective use of immunotherapies. In addition, understanding how immunotherapies are leveraged to obtain better responses in other cancer types may be useful in OC treatment approaches. A growing number of studies in OC indicate that immunotherapies targeting T-cell-based immune checkpoints might have limited benefits due to the complex nature of immune evasion mechanisms [ 12 – 16 ]. Thus, understanding the interactions of immune cells in both adaptive and innate compartments will be central to fully leveraging the promise of immunotherapeutic agents for effective OC treatment. In this review, we discuss immune regulation and evasion mechanisms in OC as identified in preclinical models (mouse and human) and human clinical trials. We also outline the outcomes of clinical trials using immunotherapies for OC treatment and potential determinants of response and resistance. Finally, we highlight novel emerging immunotherapies that have succeeded or are poised to make a significant impact on cancer treatment and their potential utility for treating patients with OC.

In recent years, innovative immunotherapeutic approaches with significant potential for cancer therapy have emerged ( Key Figure Figure 3 ). Below, we highlight novel strategies for potential OC trials.

DCs are professional antigen-presenting cells that link innate and adaptive immunity by processing and presenting antigens to T cells. In cancer, DCs can activate anti-tumor immunity but may become dysfunctional or suppressed in the tumor microenvironment, limiting their efficacy. Several studies have implicated DCs in various aspects of OC [ 52 , 64 – 68 ]. An example of the role of DCs in OC was showcased in a study conducted in an inducible p53-dependent model of aggressive ovarian carcinoma in mice [ 64 ]. This model showed the development of anti-tumor immunity starting from very early stages, which was driven by infiltrating DCs and prevented tumor growth for prolonged periods. However, at later stages, DCs underwent phenotypic switching, became immunosuppressive, and thereby promoted ovarian tumor growth. This dual function of DCs in OC was highlighted by the fact that depleting DCs early in the disease course accelerated tumor expansion, while DC depletion at advanced stages significantly delayed aggressive malignant progression. This study implicates DCs in OC growth and progression but also underscores the importance of an immunosuppressive microenvironment over tumor-intrinsic changes in tumor progression. From another angle, several studies also highlight the important role of endoplasmic reticulum (ER) stress in immunosuppression in OC [ 65 , 69 , 70 ]. For instance, interesting work explored the role of the ER stress response factor XBP1 in tDCs and its impact on OC progression [ 65 ]. Constitutive XBP1 activation in tDCs suppressed anti-tumor immunity by driving abnormal lipid accumulation through a triglyceride biosynthesis program induced by lipid peroxidation byproducts. Inhibiting XBP1 in DCs restored their immunostimulatory function in mice, enhanced type 1 anti-tumor responses, and extended animal survival. These findings highlight the therapeutic potential of targeting the ER stress response to inhibit tumor growth and bolster anti-cancer immunity by reactivating DC function.

Oncolytic viruses have shown strong clinical benefit as immunotherapeutic agents in some cancers [ 96 ] ( Key Figure Figure 3 ). Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, was the first to demonstrate therapeutic benefit against melanoma in a phase III trial NCT00769704 xi [ 96 ]. This study reported that T-VEC was well tolerated and resulted in longer median OS. The observed benefits were particularly pronounced in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. Other oncolytic viruses, such as Pexa-Vec, which is engineered to express GM-CSF and thymidine kinase, are also being tested for their ability to selectively eradicate cancer cells, while simultaneously stimulating an immune response [ 97 ]. However, no increase in clinical benefit has been observed in liver cancer patients in a phase III clinical trial ( NCT02562755 ) xii [ 97 ]. The use of oncolytic viruses that also express immunostimulatory factors is an important development because based on studies thus far, it is becoming clear that achieving long-term anti-tumor responses is key to treatment success [ 98 – 100 ]. This holds true for both T-VEC and Pexa-Vec, both of which express GM-CSF, which recruits and activates DCs and enhances T-cell responses [ 96 , 97 ]. Oncolytic viruses are also being increasingly explored for OC treatment, including the preclinical development of MEM-288, an oncolytic adenovirus encoding immune agonists IFN-β and a chimeric CD40L [ 101 ]. These immune agonists activate DCs for CD8 + T cell priming and can enhance tumor-specific antigenic responses [ 101 ]. Unlike most oncolytic viruses requiring intratumoral injection, MEM-288 induces systemic anti-tumor immunity via intraperitoneal delivery can reduce both tumor and ascites burden. A number of approaches are in the testing phase to improve the efficacy of oncolytic viruses. These include tumor-selective promoters, combination therapies with immune checkpoint inhibitors, stem cell carriers to evade immune clearance, and directed evolution to boost selectivity and potency.

A number of new and highly promising biologics have also entered the clinic for treating a wide variety of cancers including OC. These include bispecific antibodies (BsAbs) that are engineered proteins capable of simultaneously binding two distinct antigens or epitopes. These include bispecific T-cell Engager (BiTE), bispecific killer engagers (BiKE), diabody, dual-affinity re-targeting molecules (DART) and tetravalent BsAbs ( Key Figure Figure 3 ). Among several bispecific T-cell engager (BiTE) antibodies are some that are U.S.A. FDA-approved for cancer treatment and are being tested in preclinical and clinical trials for OC [ 83 – 87 ]. BiTE therapy involves using antibody constructs that simultaneously engage CD3-positive T cells and tumor-associated antigens to direct cytotoxic T cells to cancer cells. For instance, AMG 110 (solitomab) targets epithelial cell adhesion molecule (EpCAM) on cancer cells and CD3 on T cells. In recurrent or chemoresistant OC, agents such as solitomab can provide an alternative approach to targeting cancer cells that are no longer responsive to standard treatments. Furthermore, combining solitomab with immune checkpoint inhibitors might enhance efficacy by counteracting T cell exhaustion, a common feature in the OC microenvironment. The selective engagement of T cells with EpCAM-positive cells minimizes off-target effects, reducing systemic toxicity, often seen in traditional chemotherapy. However, despite showing preclinical promise, a phase I trial of solitomab was complicated by dose-limiting toxicities, likely due to off-target effects of the BiTE molecules on normal cells expressing EpCAM [ 88 ]. Another BiTE antibody targeting LYPD1/CD3 has shown potent OC suppression in humanized mouse models, suggesting its potential for clinical testing [ 89 ]. Antibody-Drug Conjugates (ADCs) combine the precision of monoclonal antibodies with potent cytotoxic agents, delivering targeted therapy to diseased cells while sparing healthy tissue ( Key Figure Figure 3 ). Mirvetuximab soravtansine, an ADC targeting folate receptor alpha (FRα) overexpressed in many OC, links a monoclonal antibody to the cytotoxic agent DM4, which disrupts microtubule assembly, causing cell death. In the Phase III MIRASOL trial ( NCT04209855 ) vii , the drug showed significant clinical benefits, as evidenced from longer overall survival (OS) compared to standard chemotherapy (16.46 months versus 12.75 months) in FRα-high, platinum-resistant OC [ 90 ]. Pending further investigation, these results suggest that mirvetuximab soravtansine might offer a meaningful improvement in response rates and survival outcomes for this patient population. Ongoing research continues to explore ADCs against various targets aiming to enhance efficacy and overcome resistance mechanisms in OC therapy.

Cell-based immunotherapies apply immune cells to target and destroy cancer. Among these, adoptive T-cell transfer (ACT), including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR) cells, and chimeric antigen receptor T (CAR-T) cells, have shown promise ( Key Figure Figure 3 ). CAR-T cells, engineered to target cancer without requiring MHC expression, have been successful in hematological cancers but face challenges in solid tumors such as OC, including the induction of the cytokine release syndrome (CRS), as well as having limited efficacy. Ongoing efforts to develop OC-specific CAR-T cells targeting antigens such as TAG-72, mesothelin, folate receptor alpha, and HER2 show encouraging preclinical results as evidenced from their ability to promote survival in mice bearing human orthotopic ovarian tumors [ 76 , 77 ]. Challenges in treating OC with CAR-T cells exist, highlighting the need for improved efficacy. A recent study implicated cytoskeletal transgelin 2 (TAGLN2) in T cell lipid metabolism, known to be essential to achieve effective immune responses [ 70 ]. Specifically, TAGLN2 promotes fatty acid binding protein 5 (FABP5) localization and function in activated CD8 + T cells, but its expression is reduced under ER stress. Enforcing TAGLN2 expression in CAR-T cells significantly enhanced their ability to eliminate metastatic OC, supporting the concept that overcoming ER stress might improve CAR-T efficacy [ 70 ]. This study provided compelling evidence that overcoming ER stress by enforcing TAGLN2 expression can enhance CAR-T cell efficacy, thus toffering a promising candidate treatment for OC. Similar to T cells, NK cells are potent cytotoxic immune cells whose function can be enhanced via CAR-NK cell engineering or via the use of NK cell activators [ 78 – 81 ]. CAR-NK cells, like CAR-T cells, are designed to target specific cancer types. Although CAR-NK cells remain to be widely used for OC treatment, several CAR-NK cell lines are in development and likely to be tested in the clinic in the near future. These include recently developed cytokine-induced memory-like NK cells targeting mesothelin, which may suppress MSLN-expressing OC cells, highlighting the potential of NK cell-based therapies in OC [ 82 ]. Similarly, a biotech company has developed CTH-401, an off-the-shelf CAR-NK product designed to target OC cells. Clinical trials are set to begin, aiming to evaluate the safety and efficacy of CTH-401 in treating OC. The results of these trials might uncover the true impact of CAR-NK cells in combating OC.

Treating OC poses significant clinical challenges due to the genetic variability and heterogeneity of both the tumor and its microenvironment [ 35 ]. These complexities are further exacerbated by significant genetic and non-genetic variability across patients, which can significantly impact therapeutic outcomes (see Outstanding Questions ) [ 35 ]. Immunotherapies, a promising class of cancer treatments, have so far shown limited effectiveness in OC clinical trials, likely due to a high degree of immune evasion and complex immune cell interactions observed in previous studies in OC [ 35 , 39 , 52 ]. Results from trials with immune checkpoint inhibitors have demonstrated that these therapies alone are insufficient to significantly improve outcomes in OC patients. This highlights the major limitations of single immune cell targeting to reverse the immune evasive state in OC. Therefore, there is an unmet need for acquiring a deeper molecular understanding of the immune evasion mechanisms at play in this disease. Leveraging this knowledge could lead to the development of rationally designed combination therapies that target multiple aspects of immune evasion and different immune cell populations might provide durable clinical benefit to OC patients. The emergence and testing of novel immunotherapeutic strategies – including CAR-T cells, CAR-NK cells, NK cell modulators, BiTEs, and cancer vaccines – may hold promise for the future of OC treatments because they may in part help overcome immune evasion mechanisms. However, achieving further therapeutic progress against this malignancy lags behind the progress seen against other solid tumors. Nevertheless, we posit that these approaches are likely to provide a new arsenal in the fight against OC, with the hope that one or a combination of these strategies can eventually overcome the resistance to T cell immune-checkpoint-based therapies characteristic of this disease.

Macrophages are multifunctional phagocytic cells of the innate immune system that are essential for antigen presentation, pathogen clearance, and orchestration of inflammatory responses [ 56 ]. They play dual roles in cancer: they can suppress tumor growth by promoting immune responses and destroying cancer cells, or they can support tumor progression [ 56 ]. Tumor-associated macrophages (TAMs) often adopt a pro-tumoral M2-like (anti-inflammatory) phenotype in the tumor microenvironment [ 57 , 58 ]. Several studies show key roles of macrophages in OC [ 59 – 62 ]. For example, inhibition of GPAA1 suppresses CD24 expression and promotes OC tumor cell phagocytosis by TAMs [ 59 ]. Similarly, another research group highlighted the direct role of extracellular matrix molecules in generating immunoregulatory macrophages that can support OC metastasis [ 60 ]. Furthermore, others have reported that reducing sialylation can improve antitumor immunity towards ovarian tumors by re-polarizing macrophages from the M2-like (pro-tumorigenic) to an M1-like (anti-tumorigenic; inflammatory) phenotype [ 61 ]. Collectively, these studies highlight the complex and opposing tumor-suppressive or tumor-promoting roles macrophages can play in OC. Similarly, a study investigated serous-cavity-associated tissue-resident macrophages , known as large peritoneal macrophages (LPMs) in OC, and identified Retinoid X Receptors (RXRs) as key regulators of LPM function [ 63 ]. RXR deficiency impaired LPM survival and reduced their accumulation in early-stage ovarian tumors, leading to decreased tumor progression in mice. These findings highlight the key role of RXR signaling in OC progression and suggest RXR as a potential therapeutic target to harness the anti-cancer potential of LPMs. Collectively, these studies emphasize the known important role of macrophages in shaping immune responses and advancing therapeutic strategies against OC.

Neutrophils are the most abundant myeloid cells that can either suppress or promote tumor growth and progression, such as by enhancing angiogenesis, facilitating metastasis, and enabling immune evasion [ 71 ]. The specific functions of neutrophils are influenced by their phenotypes, for example N1-like, which are considered tumor-suppressive, versus N2-like, which are considered pro-tumorigenic [ 71 ]. However, recent analysis of tumor-associated neutrophils showed that neutrophils, as expected, are more diverse than just the N1-like and N2-like type phenotypes [ 71 ]. Several studies have documented the role of neutrophils in cancer, including OC [ 69 , 72 – 74 ]. A recent report indicated that immature and mature neutrophils infiltrating tumors can undergo reprogramming, differentiating into distinct, long-lived T3 neutrophils expressing the surface marker dcTRAIL-R1 [ 74 ]. The study also showed that T3 neutrophils predominantly localized to a glycolytic and hypoxic niche at the tumor core and exerted pro-angiogenic functions that favored tumor growth. Furthermore, depletion of T3 neutrophils blocked tumor growth. These results suggested that neutrophils can adapt to specific tissues and environments to promote cancer, at least in this context. This also suggests that reprogrammed neutrophils might be potentially targeted to treat certain cancers, and ideally, enhance certain cancer immunotherapies. Moreover, others have directly evaluated the role of neutrophils in OC and shown that ovarian tumors can program neutrophils to inhibit T-cell anti-tumor functions by activating the ER stress sensor IRE1α [ 69 ]. This was supported by the observation that intratumoral neutrophils can exhibit hyperactivation and increased expression of ER stress response markers compared to non-tumor sites in mice [ 69 ]. Consistent with the role of IRE1α in causing an immunosuppressive environment, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 immune checkpoint blockade, leading to ovarian tumor regression and long-term survival in about half of treated mice [ 69 ].

Clinical trials show that immunotherapies have limited efficacy, if any, in OC ( Table 1 ). For example, a phase II trial (UMIN Clinical Trials Registry UMIN000005714) i with nivolumab, an anti-PD-1 antibody, in patients with platinum-resistant OC reported a modest overall response rate (ORR) of 15%, with a median progression-free survival (PFS) of 3.5 months and a median overall survival (OS) of 20 months [ 12 ]. Although this study highlighted nivolumab’s safety and potential efficacy, it also underscored the need for further improvement due to limited clinical benefits. Similarly, a nonrandomized phase II trial ( NCT02853318 ) ii evaluated the efficacy and safety of combined pembrolizumab, bevacizumab, and oral metronomic cyclophosphamide in 40 women with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer [ 13 ]. The trial reported an ORR of 47.5% and a median PFS of 10 months. The treatment was well tolerated, demonstrating clinical activity with a favorable toxicity profile [ 13 ]. However, further testing is needed to fully understand the efficacy of this combination for OC therapy. Larger phase III trials – including JAVELIN Ovarian 100, JAVELIN Ovarian 200, and IMagyn050/GOG 3015/ENGOT-OV39 – have also shown limited benefit of immunotherapy in OC [ 14 – 16 ]. Specifically, the JAVELIN Ovarian 100 trial ( NCT02718417 ) iii tested avelumab (an anti-PD-L1 monoclonal antibody) in combination with chemotherapy in newly diagnosed epithelial OC patients [ 14 ]. Despite its global scale, the trial did not support avelumab’s use in frontline treatment because of lack of added clinical benefit. PD-L1 status was evaluated in 813 patients, but the results were inconclusive, and no other biomarkers were analyzed, thus limiting the molecular response marker discovery for this regimen. Similarly, the phase III JAVELIN Ovarian 200 trial ( NCT02580058 ) iv compared avelumab alone or in combination with pegylated liposomal doxorubicin (PLD) against PLD alone in platinum-resistant or refractory OC [ 15 ]. The trial did not show significant improvement in overall survival with avelumab, although this study indicated that PD-L1 and CD8 expression might benefit some patients; however, the results were underpowered and it was not possible to reach any definitive conclusions. The phase III IMagyn050 trial ( NCT03038100 ) v tested the addition of atezolizumab (an anti-PD-L1 antibody) to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III and IV OC patients. Interim results showed no significant survival benefit from atezolizumab, further questioning the efficacy of immune checkpoint inhibitors in newly diagnosed OC [ 16 ]. Another notable open label phase II study ( NCT4015739 ) vi assessed the combination of a bevacizumab biosimilar (FKB238; an angiogenesis inhibitor), olaparib (a PARP inhibitor), and durvalumab (an anti-PD-L1 antibody) in relapsed advanced OC. Conducted in French centers, the study reported non-progression rates of 69.8% at 3 months for platinum-resistant relapse, meeting the prespecified endpoint, and 43.8% at 6 months for platinum-sensitive relapse, which did not meet the endpoint. Median PFS was 4.1 months and 4.9 months, respectively. Of note, an increased CA-125 elimination rate (KELIM-B) was associated with better survival [ 75 ]. These trials demonstrate that OC seems to be resistant to immunotherapies such as these, likely due to its highly immune-evasive nature, and this represents a significant barrier to successful treatments. Using novel strategies to render nonresponsive tumors more responsive to immunotherapies, should be a research priority to enhance the effectiveness of treatments in OC.