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<p>Despite multimodal treatment strategies, survival rates for osteosarcoma have remained stagnant, and immune checkpoint blockade targeting PD-1/PD-L1 alone has demonstrated limited clinical benefit. Tumor-associated macrophages (TAMs), which are abundant in osteosarcoma and predominantly exhibit an M2-like polarization, contribute significantly to immunosuppression, angiogenesis, metastasis, and chemotherapy resistance. This review outlines the origins and polarization dynamics of TAMs, and highlights central mechanisms through which they impair T-cell function (e.g., PD-1/PD-L1, TIM-3/galectin-9), inhibit phagocytosis (CD47/SIRPα), facilitate metastatic spread (CCL18–Wnt/β-catenin, COX-2/STAT3), and promote therapy resistance (IL-1β, extracellular vesicles). Emerging therapeutic strategies include depleting TAMs or inhibiting their recruitment (via CCL2/CCR2 or CSF1R blockade), disrupting checkpoint signals (anti-CD47/SIRPα, PD-1/PD-L1 inhibitors), and reprogramming M2 TAMs toward an M1 phenotype using pharmacological agents, nanotherapeutics, physical modalities (e.g., R848, photothermal therapy), and metabolic signaling inhibitors (PI3Kγ, ERK5). Innovative approaches such as CAR-macrophages and combined immune–vascular targeting may further amplify antitumor responses. Key challenges, including non-standardized markers, methodological variability, and spatiotemporal heterogeneity, underscore the need for a TAM-reprogramming paradigm over mere depletion, and support the integration of multi-omic spatial profiling and biomarker-driven clinical trials focused on metastatic disease. Ultimately, macrophage-targeted therapies integrated with conventional treatments hold promise for improving outcomes in osteosarcoma.</p>

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Macrophage-centered immunotherapy for osteosarcoma: mechanisms, repolarization, and translational strategies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月7日

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  • Zhide Li,
  • Dong Lin,
  • Liandi Wu,
  • Wending Xu,
  • Haibo Zhang,
  • Zhaonong Zhuang,
  • Long Zhang,
  • Jianan Chen,
  • Zhaoyuan Su

摘要

Despite multimodal treatment strategies, survival rates for osteosarcoma have remained stagnant, and immune checkpoint blockade targeting PD-1/PD-L1 alone has demonstrated limited clinical benefit. Tumor-associated macrophages (TAMs), which are abundant in osteosarcoma and predominantly exhibit an M2-like polarization, contribute significantly to immunosuppression, angiogenesis, metastasis, and chemotherapy resistance. This review outlines the origins and polarization dynamics of TAMs, and highlights central mechanisms through which they impair T-cell function (e.g., PD-1/PD-L1, TIM-3/galectin-9), inhibit phagocytosis (CD47/SIRPα), facilitate metastatic spread (CCL18–Wnt/β-catenin, COX-2/STAT3), and promote therapy resistance (IL-1β, extracellular vesicles). Emerging therapeutic strategies include depleting TAMs or inhibiting their recruitment (via CCL2/CCR2 or CSF1R blockade), disrupting checkpoint signals (anti-CD47/SIRPα, PD-1/PD-L1 inhibitors), and reprogramming M2 TAMs toward an M1 phenotype using pharmacological agents, nanotherapeutics, physical modalities (e.g., R848, photothermal therapy), and metabolic signaling inhibitors (PI3Kγ, ERK5). Innovative approaches such as CAR-macrophages and combined immune–vascular targeting may further amplify antitumor responses. Key challenges, including non-standardized markers, methodological variability, and spatiotemporal heterogeneity, underscore the need for a TAM-reprogramming paradigm over mere depletion, and support the integration of multi-omic spatial profiling and biomarker-driven clinical trials focused on metastatic disease. Ultimately, macrophage-targeted therapies integrated with conventional treatments hold promise for improving outcomes in osteosarcoma.