p53 hotspot mutants attenuate CTL-mediated tumor cell killing through a novel ALKBH5-YTHDF3-PD-L1 pathway.

TP53 is a well-documented tumor suppressor gene frequently mutated in malignancies. It has been demonstrated that the gain-of-function (GOF) mutation of p53 promotes the development and progression of cancers; however, its extrinsic oncogenic mechanisms are still poorly understood. Herein, we found that the oncogenic effect of mutant p53 in vivo is dependent on the tumor immune microenvironment. Importantly, our data demonstrated a significant increase in PD-L1 expression in cells expressing mutant p53. Consistently, subsequent investigations indicated that PD-L1 mRNA is subject to N6-methyladenosine modification, and that the reader protein YTHDF3 is required for regulating both the stability and translational output of PD-L1 mRNA in the transformed cells. The mechanistic study showed that mut-p53 inhibits the expression of demethyladenosine transferase ALKBH5, resulting in m6A-YTHDF3 mediated upregulation of PD-L1 in cancer cells and the potentiation of the immune evasion program. Furthermore, exogenous expression of ALKBH5 in mut-p53-expressing cells suppresses PD-L1 levels, enhances the antitumor immune response mediated by cytotoxic T lymphocytes (CTLs), and blocks advanced tumor growth in vivo. Thus, our study gives rise to the reasonable strategy that restoration of ALKBH5 activation or inhibition of the m6A modification-YTHDF3 axis could potentially reactivate immune surveillance and eliminate tumors harboring mut-p53.