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Despite the significant advances in the development of immune checkpoint inhibitors (ICI), primary and acquired ICI resistance remains the primary impediment to effective cancer immunotherapy. Residing in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a pivotal role in tumor progression by regulating diverse signaling pathways. Notably, accumulating evidence has confirmed that TAMs interplay with various cellular components within the TME directly or indirectly to maintain the dynamic balance of the M1/M2 ratio and shape an immunosuppressive TME, consequently conferring immune evasion and immunotherapy tolerance. Detailed investigation of the communication network around TAMs could provide potential molecular targets and optimize ICI therapies. In this review, we systematically summarize the latest advances in understanding the origin and functional plasticity of TAMs, with a focus on the key signaling pathways driving macrophage polarization and the diverse stimuli that regulate this dynamic process. Moreover, we elaborate on the intricate interplay between TAMs and other cellular constituents within the TME, that is driving tumor initiation, progression and immune evasion, exploring novel targets for cancer immunotherapy. We further discuss current challenges and future research directions, emphasizing the need to decode TAM-TME interactions and translate preclinical findings into clinical breakthroughs. In conclusion, while TAM-targeted therapies hold significant promise for enhancing immunotherapy outcomes, addressing key challenges-such as TAM heterogeneity, context-dependent plasticity, and therapeutic resistance-remains critical to achieving optimal clinical efficacy.
Yang et al. (Fri,) studied this question.