Immune-featured stromal niches associate with response to neoadjuvant immunotherapy in oral squamous cell carcinoma

Tumor stromal cells (TSCs) play a crucial yet underexplored role in the tumor microenvironment (TME). This study uses single-cell sequencing and spatial transcriptomics on paired tumor specimens from 22 patients with oral squamous cell carcinoma (OSCC) enrolled in a randomized two-arm phase 2 trial, receiving neoadjuvant anti-PD-1 mono-immunotherapy or anti-PD-1 plus docetaxel-cisplatin-5-fluorouracil (TPF) immunochemotherapy. Single-cell analysis reveals increased TSCs within the TME of responders in immunochemotherapy. Notably, significant post-treatment upregulation of SELP + high endothelial venules (HEVs) and APOD + myofibroblastic cancer-associated fibroblasts (myCAFs), alongside a decline in STMN1 + capillary endothelial cells (cECs), is specific to the immunochemotherapy cohort. In contrast, MYF5 + muscle satellite cells (MSCs) are upregulated in non-responders to mono-immunotherapy. SELP + HEVs and APOD + myCAFs foster favorable immunomodulatory stromal niches for improved outcomes, while STMN1 + cECs and MYF5 + MSCs form immunosuppressive niches in tumor invasion regions, highlighting therapeutic targets. The trial was registered at ClinicalTrials.gov , and the registration number is NCT04649476. • Two distinct stromal niches influence immunotherapy response in patients with OSCC • SELP + HEVs and APOD + myCAFs enhance immune infiltration and antigen presentation • STMN1 + cECs and MYF5 + MSCs suppress T/NK cells in the tumor microenvironment Liu et al. reveal distinct tumor stromal niches in oral squamous cell carcinoma using single-cell and spatial transcriptomics. They identify SELP + HEVs and APOD + myCAFs as immunomodulatory cell types enhancing responses to immunotherapy. In contrast, STMN1 + cECs and MYF5 + MSCs are suppressive cell types inhibiting immune reactions.