Oncogenic viruses hijack a lysosomal receptor to fuel cancer growth

Oncogenic viruses are notorious for rewiring the cells they infect, but a new study reveals an unexpectedly devious trick: commandeering one of the cell’s own protein-recycling machines to keep themselves hidden and help tumors grow. In research published in Nature Microbiology, a team led by Qiliang Cai of Fudan University reports that Kaposi’s sarcoma-associated herpesvirus, or KSHV, triggers a chemical modification of the lysosomal protein LAMP2A that supercharges a specialized degradation pathway called chaperone-mediated autophagy. The finding not only explains how the virus maintains its persistent, cancer-promoting state, but also points to a druggable vulnerability shared by several major virus-associated cancers.

Chaperone-mediated autophagy, or CMA, is distinct from the better-known bulk-recycling form of autophagy. Instead of engulfing entire cellular structures in membrane-bound vesicles, CMA operates one protein at a time. Cytoplasmic proteins carrying a specific pentapeptide recognition motif are bound by the chaperone HSC70 and delivered to the lysosomal membrane, where LAMP2A acts as the receptor. The substrate protein then unfolds and threads through a multimeric channel formed by LAMP2A molecules into the lysosomal lumen, where it is degraded. Because this pathway can selectively remove transcription factors, metabolic enzymes and signaling proteins, it has long been implicated in cancer progression, immune regulation and aging, yet how pathogens manipulate it has remained poorly understood.

The new work began with a proteomic search for proteins that associate with TRIM32, a member of the tripartite motif family of E3 ligases, during KSHV infection. Using mass spectrometry on purified TRIM32 complexes from infected cells, the researchers found that TRIM32 interacted prominently with components of the CMA machinery, including HSC70, HSP90 and LAMP2A itself. Gene ontology analysis of the interactors confirmed enrichment in chaperone-mediated autophagy and innate immune pathways. When cells were stimulated with double-stranded DNA, a molecular stand-in for viral DNA sensing, TRIM32 formed visible cytoplasmic bodies that co-localized with LAMP2A and other CMA components, and the physical interaction between TRIM32 and LAMP2A could be recapitulated with purified recombinant proteins in vitro.

The pivotal discovery concerned a post-translational modification known as SUMOylation, in which small ubiquitin-like modifier proteins, chiefly SUMO2 and SUMO3, are covalently attached to lysine residues on target proteins. SUMOylation is reversible and frequently alters a protein’s localization, interaction partners or stability, and it has well-documented roles in both viral infection and tumorigenesis. The team showed that TRIM32 acts as a SUMO E3 ligase for LAMP2A, conjugating SUMO2/3 to three specific lysines: K104, K132 and K289. Detailed mapping experiments revealed that K289 and K104 serve as primary sites for SUMO2 attachment, while a SUMO-interacting motif on LAMP2A, SIM1, facilitates SUMO3 modification at K132. The RING domain of TRIM32 proved essential for this modification.

What makes this modification so consequential is where it sends LAMP2A. Although LAMP2A is classically viewed as a lysosomal membrane receptor, the study found that SUMOylated LAMP2A accumulates in the nucleus during viral infection. This nuclear translocation of LAMP2A, driven by TRIM32-dependent SUMOylation, activates the CMA program, allowing the infected cell to selectively degrade a distinct set of client proteins. Among the consequences documented in the paper is the suppression of viral reactivation and inflammation: by keeping the lytic program damped down, the virus preserves latency, its long-term persistence strategy, while the altered cellular environment simultaneously favors tumor growth and the formation of new blood vessels, a process called angiogenesis.

Using KSHV as a model system, the researchers demonstrated in animal models that TRIM32-induced SUMOylation of LAMP2A promotes tumor growth and angiogenesis in vivo. When LAMP2A was depleted from KSHV-transformed cells, TRIM32’s ability to drive colony formation and xenograft expansion collapsed. Reconstituting the cells with wild-type LAMP2A restored tumorigenesis, but reconstitution with SUMOylation-defective mutants, in which the key lysines were changed to arginine, failed to do so. Immunohistochemical staining of the resulting tumors showed corresponding changes in markers of proliferation, endothelial content and viral lytic reactivation, tying the molecular modification directly to pathological outcomes.

Crucially, the mechanism appears not to be a quirk of KSHV alone. In tumor tissues from patients, the team found that TRIM32 expression positively correlates with LAMP2A in cancers associated with KSHV, Epstein–Barr virus and human papillomavirus, the viruses behind Kaposi’s sarcoma, nasopharyngeal carcinoma and cervical cancer, respectively. The correlation was stratified by the abundance of viral latent antigens such as LANA, EBNA1 and E6, suggesting that the burden of latent viral infection tracks with activation of this CMA-regulating axis. A pan-cancer analysis using the GEPIA database further showed coordinated TRIM32 and LAMP2A expression across a range of tumor types, hinting that the pathway may extend beyond classic tumor viruses.

Perhaps the most translationally exciting aspect of the study is the development of peptide inhibitors that target the SUMOylated form of LAMP2A. Derived from LAMP2A sequences, the peptides P3 and P7 were designed to disrupt the SUMOylation-dependent nuclear localization and function of the receptor. In cell culture, the peptides suppressed colony formation by KSHV-, EBV- and HPV-infected cancer cells at concentrations that showed minimal cytotoxicity toward uninfected cells. In mouse xenograft models, including both subcutaneous and intraperitoneal tumor systems, treatment with the peptides reduced tumor progression and angiogenesis. The antitumor effect depended on intact LAMP2A and SUMO2: the peptides lost efficacy in cells lacking LAMP2A or with SUMO2 knocked out, and in cells reconstituted with SUMOylation-site mutants, confirming that the drugs act precisely on the pathway the team had dissected.

The work also clarifies a long-standing puzzle about how oncogenic viruses balance two competing needs. Reactivating into the lytic cycle produces new viral particles but exposes the infection to immune detection and inflammatory stress, whereas permanent latency forgoes transmission. By activating CMA through SUMOylated LAMP2A, the virus appears to buy itself a stable middle ground: lytic genes stay quiet, inflammatory signaling is blunted, and the host cell survives long enough to accumulate the mutations and vascular support that a tumor requires. Earlier studies had shown that CMA is required for tumor growth and that LAMP2A is overexpressed in several malignancies, but the viral trigger and the specific enzymatic machinery, TRIM32 acting on defined lysines, had not previously been connected.

For patients with virus-associated cancers, the implications are significant. Current treatments for Kaposi’s sarcoma and related malignancies often rely on broad chemotherapy or immune modulation, and options specifically targeting the virus–host interface remain limited. A receptor like LAMP2A, positioned at the convergence of viral persistence and tumor maintenance, offers a single point of intervention with dual antiviral and antitumor potential. The peptide approach also demonstrates that blocking a specific post-translational modification, rather than the entire autophagy pathway, can achieve therapeutic selectivity, an important consideration given CMA’s normal roles in neurons, liver and immune cells. The authors have filed a provisional patent on the compositions and methods, and while peptide drugs face delivery and stability hurdles before clinical use, the study establishes LAMP2A SUMOylation as a promising and mechanistically well-defined target. As oncogenic viruses continue to account for a substantial share of cancers worldwide, understanding and interrupting the molecular hijacking they perform may prove one of the most consequential strategies in virology-driven cancer therapy.

Subject of Research: How oncogenic viral infection drives LAMP2A SUMOylation and chaperone-mediated autophagy to promote tumorigenesis

Article Title: Oncogenic viral infection triggers LAMP2A SUMOylation and chaperone-mediated autophagy to promote tumorigenesis

Article References: Oncogenic viral infection triggers LAMP2A SUMOylation and chaperone-mediated autophagy to promote tumorigenesis. (n.d.). https://doi.org/10.1038/s41564-026-02476-3

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02476-3

Keywords: KSHV, LAMP2A, TRIM32, SUMOylation, chaperone-mediated autophagy, oncogenic viruses, tumorigenesis, angiogenesis, Epstein-Barr virus, human papillomavirus, virus-host interactions, peptide inhibitors