The emerging role of ZDHHC9 in cancer: from protein palmitoylation to tumor progression and immune regulation

Abstract

Protein S-palmitoylation, and more broadly protein S-acylation when acyl donors other than palmitoyl-CoA are involved, is an emerging post-translational mechanism in cancer that dynamically regulates protein stability, membrane localization, trafficking, and signaling output. Among the zinc finger DHHC-type palmitoyl acyltransferases, ZDHHC9 has attracted increasing attention because of its expanding roles across multiple malignancies. Accumulating evidence indicates that ZDHHC9 is frequently dysregulated in cancer and contributes to tumor progression through palmitoylation-dependent regulation of proteins involved in oncogenic signaling, stress adaptation, metabolic rewiring, and immune evasion. Functionally, ZDHHC9 has been linked to the modulation of substrates such as BiP/GRP78, CD38, STAT1, PD-L1, and PCBP1, thereby influencing unfolded protein response signaling, checkpoint-related immune suppression, ferroptosis-associated pathways, and tumor cell survival. Beyond its tumor-intrinsic effects, ZDHHC9 is increasingly recognized as a regulator of the tumor immune microenvironment, with emerging evidence showing that it can suppress effector CD8+ T-cell responses and reduce sensitivity to immune checkpoint blockade in selected cancer contexts. In this review, we summarize the molecular basis of ZDHHC9, discuss its roles in tumor progression and immune regulation, and highlight current advances and challenges in therapeutic targeting. A deeper understanding of ZDHHC9-dependent palmitoylation networks may support the development of new biomarkers and precision anticancer strategies.