Molecular innate immune programs of tumor-associated macrophages in immune checkpoint blockade resistance: a staged framework from suppressive circuitry to translational bottlenecks.

Immune checkpoint blockade (ICB) has reshaped the treatment landscape for many malignancies, yet only a subset of patients achieve durable clinical benefit. Both primary and acquired resistance remain major barriers to long-term disease control. As central innate immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) have emerged as key contributors to this resistance. Beyond their well-recognized role in suppressing T-cell responses, TAMs influence stromal organization, metabolic stress, checkpoint ligand expression, and phagocytic activity within the TME. They also affect the intratumoral distribution and clearance of therapeutic antibodies. In this review, we discuss TAM-mediated resistance to ICB as a molecularly regulated innate immune process that is dynamic and adaptive. We consider how macrophages are recruited to tumors, how they are educated by local microenvironmental cues, and how innate immune signaling, metabolic regulation, and phagocytic checkpoints shape suppressive programs that limit the efficacy of ICB. This framework allows us to distinguish macrophage programs that recur across tumor types from those shaped by specific tissue contexts or tumor lineages, and to place diverse TAM subsets within a clinically relevant model of ICB resistance. We also review current TAM-directed therapeutic strategies, including CSF1/CSF1R blockade, inhibition of chemokine-dependent recruitment, metabolic and epigenetic reprogramming, targeting of phagocytosis checkpoints, and emerging delivery-based approaches. Although these strategies are supported by substantial mechanistic evidence, their clinical activity has so far been variable. This inconsistency likely reflects the marked heterogeneity and plasticity of TAMs, compensatory signaling pathways, spatial constraints within tumors, treatment-induced adaptation, toxicity, and the lack of robust biomarkers for patient selection. We propose that future TAM-directed therapies should move beyond broad macrophage depletion or nonspecific suppression. Instead, more precise approaches are needed-ones that are matched to dominant macrophage programs, informed by spatial and functional profiling, and guided by predictive biomarkers. Such strategies may help preserve beneficial innate immune macrophage functions while selectively disrupting the TAM states that sustain resistance to ICB.