Tumor-associated macrophage reprogramming in cancer: recent advances in resistance mechanisms and therapy

Tumor-associated macrophages (TAMs) are abundant, heterogeneous, and spatially organized immune cells that regulate cancer progression, immune evasion, metastasis, and therapeutic resistance. Single-cell and spatial technologies have revealed diverse TAM states shaped by ontogeny, tumor type, disease stage, cytokines, hypoxia, metabolism, epigenetic remodeling, extracellular matrix architecture, stromal interactions, extracellular vesicles, microbiome-derived signals, and therapy-induced damage. Bidirectional cancer-TAM crosstalk evolves from tumor initiation through progression and recurrence, generating tumor-specific resistance programs that suppress lymphocytes, impair antigen presentation and phagocytosis, promote angiogenesis and metabolic restriction, remodel stroma, mediate tolerogenic efferocytosis, and sustain stem-cell, metastatic, dormancy, and regenerative niches. Therapeutic strategies include blocking macrophage recruitment or survival, activating CD40/TLR/STING signaling, targeting PI3Kγ and STAT pathways, restoring phagocytosis, modulating efferocytosis, and applying metabolic, epigenetic, stromal, vascular, nanoparticle, RNA-based, microbiome-directed, and engineered-macrophage approaches. Randomized trials have established the efficacy of CSF1R inhibition in selected CSF1-driven, macrophage-dependent tumors, whereas most other TAM- or myeloid-directed strategies in conventional solid tumors have demonstrated only preliminary clinical activity or pharmacodynamic modulation without consistent durable benefit. Off-target toxicity, spatial heterogeneity, dynamic plasticity, preclinical-clinical discordance, and combination-treatment optimization remain major barriers. Biomarker-guided patient selection, longitudinal monitoring, tumor-specific targeting, and rationally sequenced combinations will be essential for converting tumor-supportive TAMs into durable antitumor effectors.