Macrophage-centered resistance programs in cancer: A unified framework for therapeutic resistance and precision immunotherapy.

Authors

Yanjun Li, Suling Xu, Huangze Xie, Qingqing Wang, Lingeng Lu, Wenxue Ma

Published in

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. Volume 90. Pages 101498. Nov 04, 2026. Epub Nov 04, 2026.

Abstract

Therapeutic resistance remains a major barrier to durable cancer control despite advances in immunotherapy, targeted therapy, cellular therapies, chemotherapy, and radiotherapy. Although tumor cell-intrinsic genetic and epigenetic alterations are well-established drivers of resistance, treatment outcomes are also shaped by dynamic interactions within the tumor microenvironment (TME). Among its stromal and immune constituents, tumor-associated macrophages (TAMs) are prominent regulators of therapeutic resistance because of their functional plasticity and capacity to integrate diverse environmental signals. Here, we introduce macrophage-centered resistance programs as an integrative framework comprising four recurrent, non-mutually exclusive functional modules: lipid-associated, matrix-remodeling, glyco-immune, and metabolic programs. These modules link tumor-derived stressors to macrophage adaptation, immune suppression, stromal remodeling, and therapeutic persistence, while allowing substantial overlap, context dependence, and dynamic interconversion. We further distinguish associative observations from mechanistic and causal evidence and examine how macrophage-associated resistance mechanisms interact with treatment-specific tumor cell-intrinsic pathways across immune checkpoint blockade, cellular therapy, targeted therapy, chemotherapy, and radiotherapy. Finally, we discuss macrophage-directed therapeutic strategies and the requirements for biomarker-guided precision immunotherapy, including clinical validation, assay standardization, and longitudinal monitoring. This framework is intended as a testable organizational model for understanding macrophage-mediated therapeutic resistance and guiding more precise macrophage-directed interventions.

PMID:
42998578
Bibliographic data and abstract were imported from PubMed on 08 Nov 2026.

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