Tescalcin is a phagocytic checkpoint driving immune escape and limiting immunotherapeutic efficacy in hepatocellular carcinoma

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Abstract

Immunotherapies achieve durable responses in several cancers but show limited efficacy in refractory hepatocellular carcinoma (HCC). The mechanisms by which hepatoma cells evade immune recognition and limit immune checkpoint blockade (ICB) efficacy are incompletely defined. Here, we identified tumor-intrinsic tescalcin (TESC) as a previously unrecognized phagocytic checkpoint that contributes to immune evasion and ICB resistance in HCC. Mechanistically, H3K4 methylation drove TESC expression in hepatoma cells, facilitating cytosolic Ca²⁺ buffering and attenuating endoplasmic reticulum (ER) stress-induced calreticulin (CALR) plasma membrane exposure, an essential “eat-me” signal. Consequently, this process abrogates membrane CALR-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells, thereby impairing antigen presentation and subsequent T-cell activation. Clinically, elevated H3K4me3-TESC signaling was a promising prognostic biomarker for poor ICB response of HCC. Importantly, in vivo disruption of this axis restored APC phagocytic function and enhanced the antitumor effects of ICB therapy. Thus, targeting TESC-driven immune escape and its underlying epigenetic regulation may restore APC function and offer a precise therapeutic strategy to enhance immunotherapy efficacy in HCC.

Authors

Jiong-Liang Wang, Jun-Cheng Wang, Yangxun Pan, Minrui He, Zhikai Zheng, Hao Zou, Tianqing Wu, Yuhan Zhang, Zili Hu, Yizhen Fu, Wei Peng, Zhenyun Yang, Li Xu, Yao-Jun Zhang, Min-Shan Chen, Dandan Hu, Jinbin Chen, Ming Zhao, Dong-Ping Chen, Zhong-Guo Zhou