Spatiotemporal dynamics of radioresistance: decoding macrophage-driven radioprotective niches through temporal-spatial reprogramming

Within the intricate tumor microenvironment (TME), tumor-associated macrophages (TAMs) engage in dynamic cross-communication with neighboring cellular and acellular components, orchestrating dual pro- and anti-tumorigenic programs, including tumor proliferation, immune suppression, angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. Radiotherapy, while inducing direct tumoricidal effects, paradoxically triggers vascular injury and inflammatory cascades that recruit and reprogram TAM populations. These radiation-educated TAMs subsequently establish therapy-resistant niches through multifaceted mechanisms, driving post-radiation tumor recurrence and treatment failure. Emerging evidence highlights that TAM polarization states critically determine therapeutic outcomes in both standalone radiotherapy and combination regimens with immunotherapy. However, translating TAM-targeting strategies into clinical practice faces substantial biological and technical challenges. In this review, we systematically analyze the spatial-temporal mechanisms underlying radiotherapy-induced TAM recruitment and radioresistance development, with particular emphasis on their bidirectional interactions with tumor cells, immune effectors, hypoxic niches, and stromal cells. Specifically, we map the therapeutic landscape by evaluating promising targets for TAM reprogramming in combination with radiotherapy and/or immune checkpoint blockade. Furthermore, we critically appraise emerging technologies for TAM manipulation in the radioimmunotherapy context, including nanotheranostics and novel therapeutic approaches. Finally, we discuss unresolved mechanistic questions, translational barriers, and strategic opportunities for developing personalized combination therapies that leverage TAM biology to overcome radioresistance. This synthesis provides a conceptual framework for rationally designing next-generation radiosensitization strategies grounded in TME immunomodulation.