PD-1 Immunotherapy Resistance Mechanism and Combination Therapy Strategy

Abstract

Programmed death receptor-1 (PD-1) immunotherapy has made breakthroughs in the treatment of a variety of malignancies (such as non-small cell lung cancer, melanoma, gastric cancer) by blocking the PD-1/PDL1 signaling pathway and reactivating the antitumor activity of tumor-infiltrating lymphocytes. However, in clinical practice, about 60%-80% of patients develop primary or acquired resistance, which usually occurs 6-12 months after treatment initiation. This severely limits its efficacy and further clinical application. This paper systematically reviewd the drug resistance mechanisms of PD-1 immunotherapy around the regulatory axis of “tumor microenvironment-immune escape-PD-1 receptor”, focusing on analyzing key factors such as tumor microenvironment disorders, abnormal activation of immune escape pathways, and abnormal regulation of PD-1 receptors. It also proposed combination treatment strategies based on different resistance mechanisms (e.g., combined blockade of multiple immune checkpoints, combination with anti-angiogenic drugs, PI3K/mTOR inhibitors, radiotherapy, and chemotherapy), aiming to provide a theoretical reference for overcoming PD-1 immunotherapy resistance.