Tumor-associated macrophages: potential therapeutic strategies and future prospects in radioresistance of cancer.

Radiotherapy is a cornerstone of cancer treatment. However, radioresistance remains a major obstacle limiting its efficacy. Tumor-associated macrophages (TAMs) are essential regulatory cells within the tumor microenvironment (TME) and exert complex, context-dependent effects on radioresistance. Rather than conforming to fixed M1/M2 phenotypes, TAMs are a plastic and heterogeneous population. Their functional states are shaped by tumor type, spatial localization, radiation dose, fractionation schedule, and time post-irradiation. This review summarizes how radiotherapy dynamically remodels the functional states of TAMs via inflammatory and chemotactic signaling, hypoxia- and lactate-associated metabolic adaptation, extracellular vesicle communication, damage-associated molecular pattern release and cyclic GMP-AMP synthase-stimulator of interferon genes signaling, and altered phagocytosis and antigen processing, in a regimen- and modality-dependent manner. TAMs can promote radioresistance by enhancing DNA damage repair, maintaining cancer stem cell-like properties, inducing aberrant angiogenesis and lymphangiogenesis, remodeling the extracellular matrix, altering metabolism, and shaping an immunosuppressive TME. Conversely, under specific radiation doses, time windows, and immunological contexts, certain TAMs may enhance tumor radiosensitivity. These effects involve increasing oxidative and nitrosative stress, impairing DNA repair, promoting vascular normalization, improving tissue oxygenation, and amplifying radiotherapy-induced antitumor immunity. Finally, this review discusses TAM-targeted strategies combined with radiotherapy, including inhibiting TAM recruitment and survival, functional reprogramming, immune checkpoint blockade, TAM depletion, and macrophage-based delivery platforms. To date, evidence mostly stems from preclinical or early clinical studies, lacking direct proof that TAM-targeted interventions enhance clinical radiotherapy efficacy. Future research should define functional signatures, optimize treatment timing, and establish safety profiles to facilitate clinical translation of TAM-targeted radioimmunotherapy.