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.