Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies

Cancer immunotherapy has redefined cancer treatment. However, the molecular and cellular basis of immune evasion and therapeutic resistance remains incompletely understood. Early immune checkpoint inhibitors have delivered significant clinical benefit, but their efficacy and durability remain limited in many patients. These limitations have driven the exploration of next-generation immune checkpoints and additional regulatory pathways that shape tumor-immune interactions. Recent advances have broadened the immune checkpoint landscape and revealed new targets. These targets operate within interconnected networks shaped by tumor-intrinsic alterations, microenvironmental cues, the microbiome, and neuroimmune crosstalk. The application of emerging technologies has enabled high-resolution dissection of immune-tumor dynamics, providing a technological foundation for improving clinical outcomes through precise patient stratification and intervention. Furthermore, distinct regulated cell deaths, including apoptosis, ferroptosis, pyroptosis, necroptosis, and alkaliptosis, are increasingly recognized as critical modulators of antitumor immunity. Harnessing these mechanisms offers a rational path toward designing targeted and controllable therapeutic strategies that enhance the efficacy and durability of cancer immunotherapy.