PRDM1+ Malignant Cells Mediate an Immunosuppressive Landscape and Resistance to Neoadjuvant Chemoradiotherapy and Immunotherapy in Esophageal Squamous Cell Carcinoma

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.