Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer

Cancer-associated fibroblasts (CAFs) play a role in response to cancer treatment and patient prognosis. CAFs show phenotypic and functional heterogeneity and differ widely in tumors of different tissue origin. Here, we use single-cell RNA sequencing of bladder cancer (BC) patient samples and report a CAF subpopulation characterized by overexpression of the urea transporter SLC14A1. This population is induced by interferon signaling and confers stemness to BC cells via the WNT5A paracrine pathway. Activation of cGAS-STING signaling in tumor cells drives interferon production, thereby revealing a link between cGAS-STING signaling and SLC14A1+ CAF differentiation. Furthermore, the inhibition of SLC14A1+ CAF formation via targeting of STAT1 or STING sensitizes tumor cells to chemotherapy. More important, BC patients with high proportions of intratumoral SLC14A1+ CAFs show cancer stage-independent poor outcome and a worse response rate to neoadjuvant chemotherapy or immunotherapy. [Display omitted] •SLC14A1+ CAFs are identified in bladder cancer•SLC14A1+ CAFs are associated with unfavorable clinical outcomes in bladder cancer•SLC14A1+ CAFs could be induced and maintained via interferon signaling•Targeting SLC14A1+ CAFs by STAT1 or STING inhibition improves therapy response Ma et al. report a CAF subpopulation characterized by SLC14A1 overexpression. The subpopulation could be induced and maintained via interferon signaling and is associated with unfavorable clinical outcomes in BC. Targeting SLC14A1+ CAFs formation via STAT1 or STING inhibition improves therapy response.