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 ( 125 I) seed implantation. Nevertheless, resistance to these treatments persists as a challenge. Here, we identified PIK3CB as a key molecule involved in the nonresponse to 125 I and immune evasion in HCC and expounded its upstream modifiers. Differentially expressed genes in HCC tissues of 125 I non-responders or responders were screened using transcriptomics sequencing. PIK3CB expression was increased in the tumors of HCC 125 I non-responders. PIK3CB knockout increased HCC cell response to 125 I 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 125 I response and inhibited the immune evasion of HCC cells. Overexpression of ASB2 enabled ubiquitination of ZBED4. ASB2 overexpression increased 125 I 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 125 I seed brachytherapy in HCC treatment.