The multi-omics landscape and clinical relevance of the immunological signature of phagocytosis regulators: Implications for risk classification and frontline therapies in skin cutaneous melanoma

Abstract Tumor-associated macrophages (TAM) have garnered considerable attention as therapeutic targets. Monoclonal antibody treatment directed against tumor antigens contributes significantly to cancer cell clearance by activating macrophages to phagocytose tumor cells. Compared to other skin malignancies, skin cutaneous melanoma (SKCM) has not yet achieved the expected clinical efficacy and prognosis, owing to its complicated genetic and molecular pathways. Therefore, we choose TAM as an entrance point. This work seeks to thoroughly evaluate the dysregulation and regulatory role of phagocytosis regulators in SKCM and elucidate their regulatory patterns in SKCM. The prognosis-related phagocytosis regulators were subtyped in this work to examine the prognostic differences between subtypes. Then, we screened prognostic factors and constructed phagocytosis-related scoring models for survival prediction using differentially expressed genes (DEGs) between subtypes. Additionally, we investigated alternative treatment options using chemotherapeutic drug response data and clinical cohort treatment data. We first characterize and generalize phagocytosis regulators in SKCM and extensively examine the tumor immune cell infiltration. We created two phagocytosis regulators related system (PRRS) phenotypes and derived PRRS scores using a principal component analysis (PCA) technique. We discovered that subtypes with low PRRS scores had a poor prognosis and decreased immune checkpoint-associated gene expression levels. We observed significant therapeutic and clinical improvements in patients with higher PRRS scores. Our findings imply that the PRRS scoring system can be employed as an independent and robust prognostic biomarker, serving as a critical reference point for developing novel immunotherapeutic methods.