Leveraging macrophage plasticity for precision-targeted tumor immunotherapy

While immunotherapy has demonstrated remarkable therapeutic potential in certain malignancies, its overall clinical efficacy remains suboptimal. Emerging evidence indicates that the tumor microenvironment (TME) plays a pivotal role in determining immunotherapy response, with tumor-associated macrophages (TAMs) - the predominant immune cell population within TME - being closely associated with poor prognosis, metastatic progression, and therapeutic resistance. Traditionally, macrophages are classified into two primary activation states: the pro-inflammatory M1 (classically activated) phenotype and the anti-inflammatory M2 (alternatively activated) phenotype. However, this binary classification system fails to fully capture the functional complexity and phenotypic plasticity of TAMs. This comprehensive review critically examines TAM heterogeneity and explores emerging subtyping paradigms beyond conventional M1/M2 dichotomization. Furthermore, we systematically examine three principal therapeutic strategies: recruitment inhibition, TAM depletion, and phenotypic reprogramming, emphasizing their synergistic potential with existing immunotherapies. These multifaceted approaches provide novel insights for developing combination therapies to overcome current limitations in cancer treatment.