Targeted Induction of Cancer Cell Necroptosis Potentiates Anti-PD-1 Immunotherapy via CD80 Activation

Insufficient infiltration or dysfunction of lymphocytes in the tumor immune microenvironment is considered to be a contributing factor to poor immunotherapy outcomes in solid tumors. Necroptosis, a form of immunogenic cell death, has attracted increasing interest because of its unique role in regulating tumor immune responses. CL-387785, a third-generation EGFR inhibitor, has been reported to inhibit tumors by regulating the cell cycle and inducing apoptosis; however, the underlying mechanisms remain unclear. In this study, we demonstrated that CL-387785 effectively suppressed the malignant phenotype of melanoma and lung cancer and confirmed that cancer cells undergo necroptosis, as evidenced by morphological and protein-level analyses. Further in vivo and in vitro experiments revealed that CL-387785 enhances tumor cell killing by immune cells by inducing CD80 expression on the tumor cell surface, thereby increasing CD8⁺ T lymphocyte function. Detailed mechanistic studies indicated that CL-387785 targets TRADD, recruiting RIPK1 to induce necroptosis in tumor cells, with subsequent nuclear translocation of NF-κB, which regulates CD80 transcription. In conclusion, our findings indicate that CL-387785 induces necroptosis in tumor cells via the TRADD/RIPK1/NF-κB/CD80 signaling pathway, thereby sensitizing tumors to anti-PD-1 therapy. These results suggest that CL-387785 is a promising candidate for increasing tumor immunotherapy efficacy.