《生命科学》 2026, 38(5): 846-858
PD-1的免疫调控机制与肿瘤免疫治疗研究进展
摘 要：
程序性死亡蛋白1（PD-1）是免疫调控的关键分子，除抑制T细胞活化的经典功能外，新近研究发现其在巨噬细胞、NK细胞及肿瘤细胞中均发挥重要作用。本文系统阐述了PD-1在不同免疫细胞亚群中的调控机制，并且进一步讨论了肿瘤细胞自身表达PD-1的现象及其在肿瘤细胞中的功能，即肿瘤细胞固有PD-1通过非免疫途径介导肿瘤双向调控：一方面通过维持肿瘤干细胞干性、促进肿瘤细胞增殖等发挥促癌作用，另一方面可产生抑癌作用。尽管PD-1/PD-L1抑制剂在多种肿瘤中展现出差异化疗效，但仍面临客观缓解率不均一、耐药及超进展等临床挑战。本文结合上述机制与临床研究进展，进一步探讨了PD-1靶向治疗的联合策略与新型药物研发，旨在为开发靶向肿瘤细胞固有PD-1的精准疗法及优化免疫治疗策略提供理论依据。
通讯作者：全纯涛 , Email:quanchuntao@126.com 谢 妮 , Email:xn100@szu.edu.cn
Abstract:
Programmed cell death protein 1 (PD-1) has emerged as a pivotal immunoregulatory molecule, whose influence extends far beyond its conventional role in inhibiting T cell activation. Recent groundbreaking research has uncovered its critical involvement in modulating the functions of various immune cell subsets, including macrophages and natural killer (NK) cells, and surprisingly, its direct expression and functional significance within tumor cells themselves. This comprehensive review aims to systematically elucidate the multifaceted regulatory mechanisms of PD-1 across diverse immune cell populations and critically examine the intriguing phenomenon of intrinsic PD-1 expression in tumor cells. We delve into how this tumor-intrinsic PD-1 can exert dual regulatory effects—either promoting or suppressing tumorigenesis —via non-immune pathways, such as influencing tumor stem cell properties, cellular proliferation, and apoptosis. Despite
the transformative impact of PD-1/PD-L1 inhibitors in cancer therapy, their efficacy varies significantly across different tumor types, highlighting the complex interplay within the tumor microenvironment and the emergence of resistance mechanisms. This review synthesizes current understanding of these differential therapeutic outcomes and addresses key challenges, including primary and acquired resistance, and the risk of hyperprogressive disease (HPD). We discuss various resistance mechanisms, such as antigen presentation defects, the formation of suppressive tumor microenvironments, the activation of alternative immune checkpoints, and oncogenic pathway abnormalities. Furthermore, we explore innovative strategies to overcome these limitations, including combination therapies involving PD-1 antibodies with anti-angiogenic drugs, LAG-3 inhibitors, or bispecific antibodies targeting PD-1/VEGF, which hold immense promise in enhancing anti-tumor immunity and combating resistance. The review also highlights emerging research directions, particularly targeting tumor-intrinsic PD-1 with small molecule inhibitors to inhibit tumor stemness and proliferation via downstream signaling pathways. We emphasize the potential of multi-modal approaches combining PD-1 antibodies with small molecule inhibitors or mTOR pathway inhibitors to synergistically modulate both tumor cells and the immune microenvironment. Moving forward, a deeper understanding of the PD-1 signaling networks within specific cancer types and cell subtypes is crucial. We propose that future research should focus on deciphering these intricate networks to develop highly specific targeted therapies and combination regimens, coupled with the establishment of predictive biomarker systems. This approach will be instrumental in advancing tumor immunotherapy towards more broad-spectrum, efficient, and precise clinical applications, ultimately benefiting a wider patient population by overcoming current therapeutic hurdles and fostering sustained anti-tumor responses.
Communication Author：QUAN Chun-Tao , Email:quanchuntao@126.com XIE Ni , Email:xn100@szu.edu.cn
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