Heterogeneity of macrophages in PD-1/PD-L1 inhibitor therapy: a single-cell perspective

Therapeutic blockade of the PD-1/PD-L1 signaling pathway is the focus of tumor immunotherapy. However, drug resistance and irAEs induced by PD-1/PD-L1 inhibitors have emerged as major limitations affecting survival outcomes in patients with cancer. Macrophages are not only the core immune cells that regulate tumor progression and metastasis, but also the key factors that affect the therapeutic effect of PD-1/PD-L1 inhibitors, thus showing significant clinical value in optimizing immunotherapy strategies. scRNA-seq technology has provided powerful analytical tools and precise biological insights to decipher macrophage heterogeneity, further elucidating disease-specific macrophage subpopulations with distinct gene signatures and functional plasticity during PD-1/PD-L1 blockade therapy. These advances have paved the way for better understanding the mechanisms underlying immunotherapy-induced toxicities and identifying novel predictive biomarkers. Herein, we comprehensively summarize the multifaceted functional roles of macrophages in PD-1/PD-L1 inhibitor-mediated antitumor efficacy, drug resistance and irAEs from a single-cell perspective, and the potential value of targeting macrophages to improve the accuracy of immunotherapy.