Work

A matrix stiffness gene signature identifies SLC20A1 as a novel mechano-immunological checkpoint enabling synergistic immunotherapy in pancreatic ductal adenocarcinoma

Year: 2025

Type: article

Abstract: Matrix stiffness is a defining feature of pancreatic ductal adenocarcinoma (PDAC) and drives malignant progression through mechanisms that remain poorly understood. Using an ensemble machine learning approach, we integrated multiomics data from 886 patients with mechano-biology models to develop a nine-gene matrix stiffness-associated gene signature (MSAGS). MSAGS demonstrated superior prognostic accuracy in independent cohorts, outperforming 87 existing signatures. We identified SLC20A1 within MSAGS as a novel mechano-immunological checkpoint where matrix stiffness activates an SLC20A1-STAT3 positive feedback loop, driving dual immunosuppression via TGF-β1-mediated CD8+ T-cell exclusion and PD-L1-induced T-cell dysfunction. Importantly, targeting SLC20A1 synergized with anti-PD-L1/TGF-beta bispecific antibody (BiTP, Y101D), enhancing tumor suppression and extending survival in orthotopic PDAC models by increasing the infiltration and function of cytotoxic CD8+ T cells. This work establishes MSAGS as a clinically translatable prognostic tool and positions SLC20A1 targeting as a transformative strategy to overcome PDAC immunotherapy resistance, thereby repositioning matrix stiffness as a druggable target.

Source: Cancer Immunology Immunotherapy

DOI: 10.1007/s00262-025-04195-w

Authors: Chuanbing Zhao, Yu Lu, Long He, Yunpeng Zhang, Tao Yin

Institutions: Wuhan Union Hospital, Huazhong University of Science and Technology

Language: English

Topic: Pancreatic and Hepatic Oncology Research

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,590