PIK3CB depletion restores immunosurveillance and enhances radioactive iodine response in hepatocellular carcinoma.

Authors

Yuanren Gao, A Rouhan, Wenbo Wang, Tengchuang Ma, Yali Cui

Published in

Cell biology and toxicology. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Hepatocellular carcinoma (HCC) has a high incidence and mortality rate despite the existence of various treatments, including iodine-125 (¹²⁵I) seed implantation. Nevertheless, resistance to these treatments persists as a challenge. Here, we identified PIK3CB as a key molecule involved in the nonresponse to ¹²⁵I and immune evasion in HCC and expounded its upstream modifiers. Differentially expressed genes in HCC tissues of ¹²⁵I non-responders or responders were screened using transcriptomics sequencing. PIK3CB expression was increased in the tumors of HCC ¹²⁵I non-responders. PIK3CB knockout increased HCC cell response to ¹²⁵I and inhibited tumor growth. PIK3CB induced PD-L1 expression to support the evasion of HCC cells from CD8⁺ T cells and NK cells-mediated immunosurveillance. The binding of ZBED4 at the PIK3CB promoter induced transcription of PIK3CB, and the knockout of ZBED4 enhanced the ¹²⁵I response and inhibited the immune evasion of HCC cells. Overexpression of ASB2 enabled ubiquitination of ZBED4. ASB2 overexpression increased ¹²⁵I sensitivity and inhibited immune evasion in HCC, which was reversed by overexpression of ZBED4 or PIK3CB. Consequently, these findings offer significant insights into the ASB2/ZBED4/PIK3CB regulatory axis, illuminating the potential for enhancing the efficacy of immune checkpoint blockade and ¹²⁵I seed brachytherapy in HCC treatment.

PMID:
42440198
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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