Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma

Cancer-associated fibroblasts (CAF) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against protumorigenic CAFs. In this study, using single-cell RNA sequencing on patient samples of esophageal squamous cell carcinoma (ESCC), we identified a CAF subcluster associated with tumor stemness that was enriched in genes associated with hypoxia and senescence. The CAF subpopulation, termed as hypoxia-induced senescent fibroblasts (hsCAF), displayed high secretion of insulin-like growth factor 1 (IGF1). The hsCAFs inhibited AMP-activated protein kinase (AMPK) activity in cancer cells via IGF1 to promote tumor stemness. The formation of hsCAFs was induced by the synergetic effect of hypoxia and cancer cells. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer cells under hypoxia drove IL1α production to trigger CAF senescence and IGF1 secretion via nuclear factor I A. Knockout of IGF1 in CAFs or nuclear factor erythroid 2-related factor 2 in ESCC cells suppressed the tumor growth and chemotherapy resistance induced by CAFs in vivo. Importantly, patients with high proportions of hsCAFs showed poor survival and a worse response to chemotherapy. In summary, these findings identify a hsCAF subpopulation generated by interplay between cancer cells and CAFs under hypoxic conditions that promotes ESCC stemness and reveal targeting hsCAFs as an effective therapeutic strategy against chemotherapy-resistant ESCC. Significance: A hypoxic microenvironment and cancer cells cooperate to induce a senescent fibroblast subset that supports tumor stemness, suggesting that targeting this cancer-associated fibroblast subpopulation is a potential therapeutic strategy to overcome chemoresistance.