The Efferocytosis-Driven Macrophage Polarization: A Concerto in the Tumor Immunosuppressive Microenvironment

Efferocytosis plays a critical role in maintaining tissue homeostasis and controlling inflammation. However, in the tumor microenvironment, this process is hijacked to promote immune suppression. Treatments like radiotherapy and chemotherapy lead to widespread tumor cell death, which triggers efferocytosis and drives macrophages into an immunosuppressive state, allowing the tumor to evade the immune system and resist treatment. Nonetheless, the way efferocytic signals alter macrophage function and promote protumor effects during the recognition, engulfment, and digestion of apoptotic cells remains largely unclear. Therefore, this review thoroughly examines the influence of signaling molecules during the three stages of efferocytosis on macrophage phenotype and function. Subsequently, we explore the impact of polarized M2-type macrophages on shaping the immunosuppressive tumor microenvironment and regulating the development of drug resistance. Additionally, we critically evaluate the current status of clinical translation of efferocytosis receptor-related drugs and analyze the potential reasons for their synergistic or antagonistic interactions with chemotherapy and immunotherapy. This study provides a comprehensive understanding of the regulatory mechanisms of efferocytosis in macrophage polarization, enhancing knowledge of the fundamental mechanisms underlying tumor immune evasion and offering important guidance for the development of anticancer therapies targeting the efferocytosis process.