BIRC3 deficiency blocks the ubiquitination and degradation of GOT2 to impede antitumor immune responses in lung squamous cell carcinoma.

In lung squamous cell carcinoma (LUSC), the proportion of exhausted CD8⁺ T cells is considerably higher than in lung adenocarcinoma (LUAD). The exhaustion of CD8⁺ T cells is responsible for the failure of immunotherapies, as terminally exhausted CD8⁺ T cells do not respond to immune checkpoint blockade. Therefore, investigating the regulatory mechanisms underlying CD8⁺ T-cell exhaustion in LUSC is essential for potentiating the efficacy of immunotherapy in this context. In our study, cellular assays revealed that elevated expression of GOT2 in LUSC reinforced the exhaustion of cocultured CD8⁺ T cells, as evidenced by elevated levels of TIGIT and TIM-3, while simultaneously impairing tumor-killing capabilities, as indicated by reduced LDH activity and diminished apoptosis. Animal experiments confirmed that knockdown of GOT2 effectively curbed tumor growth and boosted the CD8⁺ T cell infiltration and tumor-killing function. Mechanistic studies demonstrated that BIRC3, acting as an E3 ubiquitin ligase, can recognize the 366-372 sequence of GOT2, mediating its ubiquitination and degradation. The deficiency of BIRC3 in LUSC interrupted ubiquitination and subsequent degradation of GOT2, leading to elevated GOT2 protein levels, which in turn facilitated CD8⁺ T-cell exhaustion and ultimately compromised their antitumor immune responses. Collectively, our findings elucidated the regulatory role of protein ubiquitination in CD8⁺ T cell functionality, highlighting a novel approach to enhance the sensitivity of LUSC to immunotherapy through the intervention of the BIRC3/GOT2 ubiquitination axis. © 2025 The Pathological Society of Great Britain and Ireland.