Editorial: Overcoming resistance to immune checkpoint inhibitors: mechanisms and strategies in cancer therapy

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies designed to enhance antitumor immunity by targeting negative regulatory pathways, most notably CTLA-4 and PD-1/PD-L1, which tumors exploit to evade immune surveillance. By blocking these inhibitory signals, ICIs can reactivate T-cell-mediated antitumor responses and promote tumor cell killing.This Research Topic explores the major biological and molecular mechanisms underlying resistance to immunotherapy, their clinical implications, and potential innovative therapeutic strategies.ICIs have redefined the management of multiple malignancies and, in several settings, have significantly improved patient prognosis. They are now increasingly incorporated into multimodal cancer treatment strategies alongside chemotherapy, radiotherapy, and surgery.Nevertheless, a substantial proportion of patients exhibit primary resistance from the outset or eventually develop acquired resistance after an initial response. In fact, ICIs display considerable variability in outcomes, with approximately 20-40% of patients achieving durable responses to PD-1/PD-L1 monotherapy and combination anti CTLA-4/PD-1 therapy, still leaving more than half of patients without durable benefit.In this context, the case reported by Yang et al. 1 provides a real-world example of an innovative later-line approach in advanced Non-Small-Cell-Lung Cancer (NSCLC), in which the bispecific PD-