Oligoclonal tumor-specific CD8 T-cell revival and IRE1α/XBP1-GDF15-mediated immunosuppressive niches determine neoadjuvant chemoimmunotherapy efficacy in cervical cancer

Background Neoadjuvant chemoimmunotherapy (NACI) shows promise for locally advanced cervical cancer (LACC), but drug-tolerant persister (DTP) cells and immunosuppressive microenvironmental adaptations limit clinical efficacy. The underlying determinants governing heterogeneous responses to NACI regimens remain poorly understood, particularly regarding how dynamic tumor-immune interactions shape therapeutic outcomes. Methods We characterized microenvironmental dynamics in patients with LACC by integrating single-cell RNA sequencing (RNA-seq), single-cell VDJ sequencing (n=10, five paired pre-NACI/post-NACI samples) and spatial transcriptomics (ChiCTR2300072535). Pathological response was assessed using major pathological response criteria. The findings were validated in an independent NACI cohort (n=23 with RNA-seq), multiplex immunohistochemistry (mIHC) analysis of six surgically resected specimens, as well as functional in vitro and murine models. Results MPR patients exhibited cytotoxic revival via oligoclonal expansion of tumor-reactive CD8+T cell clones and CCR5-mediated myeloid-T cell crosstalk. Conversely, non-MPR tumors exhibited endoplasmic reticulum (ER) stress-adapted DTP cells with elevated ER stress signaling, accompanied by a deficiency in tumor-specific T-cell clone expansion and an accumulation of transforming growth factor beta receptor 2 (TGFBR2) + myeloid DTP niches. Mechanistically, ER stress signaling via the inositol‑requiring enzyme 1 alpha (IRE1α) / X‑box binding protein 1 (XBP1) axis induces growth differentiation factor 15 (GDF15) production in DTP cells, contributing to treatment‑resistant microdomains. Pharmacological IRE1α inhibition synergized with chemoimmunotherapy to eradicate DTP populations in murine models. Conclusions This study provides critical insights that NACI resistance stems from adaptive ER stress signaling in DTP cells and spatially organized immunosuppressive networks. Targeting the IRE1α/XBP1-GDF15 axis represents an actionable strategy to reprogram microenvironmental ecology and improve immunotherapy outcomes.