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Centrosome aberrations are a common feature in human cancer cells. Our previous studies demonstrated that the centrosomal protein Tax1 binding protein 2 (TAX1BP2) inhibits centrosome overduplication and is underexpressed in hepatocellular carcinoma (HCC). Here, we report that Intratumoral TAX1BP2 promotes tumor lymphocyte infiltration and enhances the efficacy of anti-PD-1 therapy. Clinically, we discovered that a hallmark of low TAX1BP2 expression in HCC tumors is T cell exclusion, whereas re-depression of TAX1BP2 in preclinical models restores antitumor immunity and potentiates anti-PD-1 efficacy. Mechanistically, we identified that reconstitution of intratumor TAX1BP2 triggers the type I interferon (IFN-I) response and subsequent facilitation of a subtype of CD27+CD8+ T cell recruitment. Furthermore, we demonstrated that Intratumor TAX1BP2 upregulates STING by inhibiting the hyperactivation of DNMT1, and EZH2 is linked to endogenous LKB1 activity., Competing Interests: Declaration of interests The authors declare that they have no conflicts of interest., (Copyright © 2025 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs affect metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) more than viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development., (© 2024 Teo et al.)