Guoxin Ren

The efficacy of immunotherapy in unresectable/recurrent/metastatic head and neck squamous cell carcinoma (U/R/M HNSCC) remains suboptimal compared with primary untreated resectable HNSCC. The immunologic and stromal landscape during immunotherapy in U/R/M HNSCC is crucial for understanding drug resistance mechanisms. In this study, single-cell RNA sequencing was performed on 42 pre- and posttreatment samples from patients in our prospective trial (NCT05156970) who received immunochemotherapy. A subset of myofibroblasts expressing CD266 was identified as hampering the response to immunochemotherapy in patients with U/R/M HNSCC. This distinct subtype of cancer-associated fibroblasts (CAF) enhanced extracellular matrix (ECM) stiffness and cellular tension through a PIEZO1-mediated biomechanical mechanism, spatially segregated CD8+ T-cell infiltration to establish immune-excluded niches, and ultimately facilitated immune evasion. Mechanistically, PIEZO1 inhibition suppressed YAP activation and reduced FAK phosphorylation, thereby mitigating matrix remodeling effects driven by myofibroblastic CAF CD266. We also observed that PIEZO1 inhibition had a synergistic effect with PD-1 blockade in HNSCC in vivo. In summary, our findings reveal an immunosuppressive mechanism in which stromal cells regulate ECM stiffness, presenting a potential therapeutic target for U/R/M HNSCC.

Single-cell transcriptomic landscape of OSCC across 19 patients.

YAP nuclear localization in CAF regions and tumor area.

χ2 analysis comparing cell-type distributions across clinical groups.

TNFRSF12A expression in HNSCC tumor tissues, matched adjacent nonmalignant tissues, and normal human tissues using public datasets.

The efficacy of immunotherapy in unresectable/recurrent/metastatic head and neck squamous cell carcinoma (U/R/M HNSCC) remains suboptimal compared with primary untreated resectable HNSCC. The immunologic and stromal landscape during immunotherapy in U/R/M HNSCC is crucial for understanding drug resistance mechanisms. In this study, single-cell RNA sequencing was performed on 42 pre- and posttreatment samples from patients in our prospective trial (NCT05156970) who received immunochemotherapy. A subset of myofibroblasts expressing CD266 was identified as hampering the response to immunochemotherapy in patients with U/R/M HNSCC. This distinct subtype of cancer-associated fibroblasts (CAF) enhanced extracellular matrix (ECM) stiffness and cellular tension through a PIEZO1-mediated biomechanical mechanism, spatially segregated CD8+ T-cell infiltration to establish immune-excluded niches, and ultimately facilitated immune evasion. Mechanistically, PIEZO1 inhibition suppressed YAP activation and reduced FAK phosphorylation, thereby mitigating matrix remodeling effects driven by myofibroblastic CAF CD266. We also observed that PIEZO1 inhibition had a synergistic effect with PD-1 blockade in HNSCC in vivo. In summary, our findings reveal an immunosuppressive mechanism in which stromal cells regulate ECM stiffness, presenting a potential therapeutic target for U/R/M HNSCC.

Mucosal melanoma (MM), an aggressive melanoma subtype arising in mucosal tissues, displays resistance to therapies effective in cutaneous melanoma. To understand how mucosal microenvironment contributes to treatment nonresponsiveness, we performed integrative analysis of single-cell and bulk messenger RNA sequencing data derived from oral mucosa–originated melanoma and revealed that mucosa-specific inflammation induces enrichment of low-pigmented neural crest–like cancer cell, mediated by COX2 ⁺ macrophages and their secretome. Maintenance of this inflammation-induced neural crest–like state in cancer cells depends on HER2 and HER3 activation. Inhibition of HER2/3 by pan-HER inhibitors blocks cell state plasticity and overcomes chemoresistance in primary MM cell lines and patient-derived xenograft (PDX) models. These findings provide insights into how the tissue of origin determines cancer aggressiveness, highlight the role of mucosal inflammation in driving melanoma stemness and chemoresistance, and advance the identification of effective treatment options currently lacking for patients with MM.

Introduction: Oral mucosal melanoma (OMM) is a rare subtype of melanoma but exhibits highly invasive biological behavior. Programmed cell death protein 1 (PD‐1) monotherapy showed lower response in OMM than other subtypes of melanoma. Materials and Methods: We retrospectively analyzed the efficacy and safety of pembrolizumab with anlotinib in patients with advanced OMM between August 2018 and September 2024. The primary endpoint was objective response rate (ORR); the secondary endpoints included disease control rate (DCR), duration of response (DOR), progression‐free survival (PFS), overall survival (OS), and treatment‐related adverse events (TRAEs). Results: Forty‐one patients were enrolled in our study. Seventeen patients (41.4%) achieved an objective response. The median PFS was 6.4 months (95% confidence interval [CI], 4.5–8.3 months), and the median OS was 10.0 months (95% CI, 8.3–11.7 months). Thirty‐three patients (80.5%) experienced at least one TRAE. The most common TRAEs were hypertension (29.3%), hand‐foot syndrome (19.5%), and anemia (19.5%). Grade 3 or higher TRAEs occurred in two patients (4.8%), and no grade 5 TRAEs were observed. Conclusions: Our study suggested that pembrolizumab with anlotinib in patients with advanced OMM showed potential efficacy and manageable adverse effects. Further studies are needed to confirm the efficacy of this combination strategy.