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

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.