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

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 abrogated membrane CALR-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and DCs, thereby impairing antigen presentation and subsequent T cell activation. Clinically, we found that elevated H3K4me3-TESC signaling was a promising prognostic biomarker for a poor ICB response in HCC. Importantly, in vivo disruption of this axis restored APC phagocytic function and enhanced the antitumor effects of ICB therapy. Therefore, targeting TESC-driven immune escape and its underlying epigenetic regulation may restore APC function and offer a precise therapeutic strategy to enhance immunotherapeutic efficacy in HCC.