ABSTRACT The mechanisms underlying resistance to neoadjuvant immunotherapy and chemoradiotherapy (nICRT) in locally advanced esophageal squamous cell carcinoma (ESCC) remain poorly understood. Through a single‐arm phase II trial ( n = 22) with 44.4‐month median follow‐up, we observed a significant survival disparity: patients achieving major pathologic response (MPR) exhibited superior 3‐year event‐free survival (EFS) and overall survival (OS), with no recurrence in MPR patients versus 71.4% recurrence in non‐major pathological response (NMPR) patients (HR = 17.69, 95% CI 2.25–139.20, p = 0.0063). Integrating single‐cell RNA/TCR sequencing and functional validation, we identified a PRDM1+ malignant cell subcluster enriched in NMPR patients and associated with treatment resistance. These cells exhibit strong lipid peroxidation characteristics, a state linked to the transcriptional activation of CTSB and MFSD12 mediated by PRDM1. This state renders the PRDM1+ malignant cell cluster more susceptible to ferroptosis induction. PRDM1+ cells further recruited immunosuppressive regulatory T cells (Tregs) through IL1A‐IL1R2 interactions and activated lipid‐metabolizing TREM2+ macrophages via CD47‐SIRPA signaling, fostering an immune‐evasive microenvironment. Conversely, MPR patients displayed expanded cytotoxic T‐effector clones with enhanced tumor‐killing capacity. Our findings identify PRDM1 as a key factor associated with nICRT resistance and suggest that targeting ferroptosis pathways or disrupting PRDM1+ cell‐mediated immune suppression may represent a viable strategy in ESCC. Clinical trial registration number: NCT03940001.
Shen et al. (2026) studied this question.
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