Oncogenic viral infection triggers LAMP2A SUMOylation and chaperone-mediated autophagy to promote tumorigenesis.

Chaperone-mediated autophagy (CMA) is a critical regulator of cancer progression and antiviral responses, often modulated by post-translational modifications. SUMOylation, a reversible post-translational modification, is implicated in viral infection and tumorigenesis, yet its role in CMA regulation remains unclear. Here we demonstrate that oncogenic viruses hijack CMA by inducing nuclear localization and SUMOylation of lysosomal-associated membrane protein 2A (LAMP2A), a central lysosomal receptor. Specifically, tripartite motif containing 32 (TRIM32) mediates SUMO2/3 conjugation to LAMP2A at lysine residues K104, K132 and K289. Using Kaposi's sarcoma-associated herpesvirus as a model, we found that TRIM32-induced LAMP2A SUMOylation activates CMA, thereby promoting viral persistence, tumour growth and angiogenesis in vivo. Importantly, TRIM32 expression positively correlates with LAMP2A in tumour tissues from patients with Kaposi's sarcoma-associated herpesvirus-, Epstein-Barr virus- and human papillomavirus-associated cancers, and peptide inhibitors targeting SUMOylated LAMP2A demonstrate potent antitumour and antiviral efficacy in vitro and in mice. Together, our findings position LAMP2A as a promising druggable target for treating virus-associated cancers.