PD-1+/PD-L1+macrophages across diseases: a translational continuum from biomarkers to immunotherapeutic targets.

Abstract

Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are critical immune checkpoints that dynamically maintain the balance between immune tolerance and immune activation. Immune checkpoint blockade targeting the PD-1/PD-L1 axis can restore T cell-mediated antitumor immunity and has shown remarkable clinical efficacy in the treatment of various solid tumors. However, owing to the complexity of the underlying mechanisms and the limitations of current predictive biomarkers, only a subset of patients derives durable benefit from this therapy. Although conventional paradigms have primarily regarded T lymphocytes as the main effectors of PD-1/PD-L1 signaling, accumulating evidence indicates that macrophages also play indispensable roles in shaping PD-1/PD-L1-mediated immunosuppressive tumor microenvironments, thereby extending the traditional understanding of this pathway. A deeper understanding of the functional roles and regulatory mechanisms of PD-1+/PD-L1+ macrophages in specific immune contexts is therefore essential for optimizing immunotherapeutic outcomes. In this review, we comprehensively summarize the regulatory mechanisms governing PD-1/PD-L1 expression in macrophages and their biological functions, and discuss the potential of PD-1+/PD-L1+ macrophages as prognostic biomarkers and therapeutic targets, and further examine targeted intervention strategies for this macrophage subset as well as their clinical diagnostic value.