Harnessing necroptosis via RIPK1 degradation to potentiate radio-immunotherapy in cervical cancer.

Immune checkpoint inhibitors (ICIs) are first-line therapy for cervical cancer (CC), yet their efficacy is limited to a subset of patients owing to low tumor immunogenicity. Single-cell RNA sequencing revealed that CC patients exhibiting robust immune responses following radiotherapy (RT) showed upregulation of necroptosis along with lower baseline RIPK1 expression. In vitro and in vivo experiments further illustrated that RT alone upregulates RIPK1 expression. Inspired by these findings, we developed a hafnium (Hf)-based nanoscale metal-organic framework loaded with LD4172, a RIPK1 degrader (LD4172/Hf). The combination of RT and LD4172/Hf effectively induced necroptosis, and elicited a potent immune response via triggering necroptosis-mediated immunogenic cell death (NICD). This effect was characterized by enhanced macrophage infiltration and phagocytosis, increased M1 polarization, reduced M2 polarization, and improved antigen presentation capacity in macrophages. Furthermore, combined RT + LD4172/Hf with PD‑1 blockade amplified the anti‑tumor immunity driven by NICD. This combined treatment nearly doubled the production of tumor-killing cytokines (IFNγ and GZMB) in CD8+ T cells and promoted the expansion of CD44⁺ effector memory T cells upon tumor rechallenge, compared with RT plus PD-1 blockade alone, thereby enabling efficient tumor elimination and conferring protection against tumor relapse. Collectively, these findings position LD4172/Hf in combination with radio-immunotherapy as a promising therapeutic strategy for CC patients.