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ResearchIn-Press PreviewHepatologyImmunologyOncology Open Access | 10.1172/JCI200415

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

Jiong-Liang Wang,1 Jun-Cheng Wang,1 Yangxun Pan,1 Minrui He,1 Zhikai Zheng,1 Hao Zou,1 Tianqing Wu,1 Yuhan Zhang,1 Zili Hu,1 Yizhen Fu,1 Wei Peng,1 Zhenyun Yang,1 Li Xu,1 Yao-Jun Zhang,1 Min-Shan Chen,1 Dandan Hu,1 Jinbin Chen,1 Ming Zhao,2 Dong-Ping Chen,3 and Zhong-Guo Zhou1

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Wang, J. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Wang, J. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Pan, Y. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by He, M. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Zheng, Z. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Zou, H. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Wu, T. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Zhang, Y. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Hu, Z. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Fu, Y. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Peng, W. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Yang, Z. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Xu, L. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Zhang, Y. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Chen, M. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Hu, D. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Chen, J. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Zhao, M. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Chen, D. in: PubMed | Google Scholar

1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

3MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Find articles by Zhou, Z. in: PubMed | Google Scholar

Published April 2, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI200415.
Copyright © 2026, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 2, 2026 - Version history
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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.

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