The double-edged sword role of tumor-associated macrophages: preventing or causing resistance to immunotherapy

Abstract Immunotherapy has transformed cancer treatment, yet only a subset of patients achieves durable responses. Although macrophages play a key role in modulating immune response and could be used to enhance immunotherapy response, accumulating evidence highlights tumor-associated macrophages (TAMs) as both preventors or mediators of cancer, and its related therapies. TAMs contribute to resistance through multiple mechanisms, such as promoting T-cell exclusion, suppressing antitumor immunity via immunoregulatory cytokines, engaging metabolic checkpoints, and facilitating tumor angiogenesis. Clinical and single-cell transcriptomic studies further underscore the association between high TAM infiltration and poor immunotherapy outcomes. Emerging therapeutic strategies aim to reprogram, deplete, or block recruitment of TAMs, with several approaches currently being evaluated in early-phase clinical trials. This review summarizes the double-edged sword of TAMs M1-like proinflammatory or M2-like immunosuppressive states, in causing or preventing cancer. A deeper understanding of TAM heterogeneity and dynamics may enable the rational design of combination therapies and the development of predictive biomarkers to guide personalized immunotherapy.