6116 Background: Hypopharyngeal squamous cell carcinoma (HPSCC) has a poor prognosis. Although neoadjuvant chemoimmunotherapy (nCIT) is promising, responses are heterogeneous and PD-L1 combined positive score (CPS) inadequately stratifies benefit. We sought biomarkers to guide patient selection. Methods: In this prospective, single-center, single-arm phase II trial, patients with resectable locally advanced HPSCC received two cycles of neoadjuvant toripalimab, albumin-bound paclitaxel, and nedaplatin. The primary endpoint was the pathological complete response (pCR) rate. Pre-treatment tumor biopsies from a subset of patients (n=13) were analyzed by single-cell RNA sequencing (scRNA-seq) to identify determinants of response. Findings were validated in a larger cohort (n=60) using bulk RNA sequencing and immunohistochemistry. Results: Among 70 evaluable patients, the objective response rate was 82. 7%. Of the 64 patients who underwent surgery, the pCR rate was 29. 7% (95% CI, 18. 9%–42. 7%). Baseline PD-L1 CPS was not associated with pathological response (P=0. 313). Single-cell analysis revealed that the pre-treatment tumor microenvironment of responders was significantly enriched with a pro-inflammatory neutrophil subset characterized by high expression of CCL3 (NeuCCL3). A gene signature score derived from this subset was a strong and independent predictor of pCR (AUC = 0. 788), significantly outperforming PD-L1 CPS (AUC = 0. 621). Conclusions: The efficacy of nCIT in HPSCC is predetermined by a baseline immune architecture orchestrated by a CCL3+ neutrophil subset. The NeuCCL3 gene signature is a promising, clinically translatable biomarker that can fill a critical gap in precision immunotherapy for HPSCC. Clinical trial information: ChiCTR2400081826.
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