Work

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

Year: 2026

Type: article

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.

Source: Advanced Science

DOI: 10.1002/advs.202515207