The UBA1–STUB1 Axis Mediates Cancer Immune Escape and Resistance to Checkpoint Blockade

Abstract

How cancer cells escape immune surveillance and resist immune checkpoint blockade (ICB) remains to be fully elucidated. By screening candidate genes frequently gained in cancer, we identified expression of ubiquitin-like modifier-activating enzyme 1 (UBA1) as being the most negatively correlated with signatures related to effector CD8+ T cells. High UBA1 expression was strongly predictive of treatment resistance and poor survival in ICB cohorts. Functional studies revealed that UBA1 mediated immune escape to promote tumor growth. Immune profiling further showed that Uba1 overexpression or depletion markedly decreased or increased functional intratumoral CD8+ T cells, respectively. Importantly, a selective UBA1 inhibitor, TAK-243, significantly synergized with ICB in multiple syngeneic models. Mechanistically, depletion or inactivation of the UBA1–STUB1 axis stabilized a key IFN pathway component (JAK1), enhanced IFN signaling, and elevated key immune modulators, including CXCL9, CXCL10, and MHC class I. Our study warrants clinical evaluation of the combination of UBA1 inhibitors and ICB. Significance: Our study reveals UBA1 as a predictive biomarker for clinical outcomes in ICB cohorts, mediating cancer immune evasion and ICB resistance. We further highlight JAK1 stabilization as a key mechanism of UBA1 inhibition and nominate the UBA1–STUB1 axis as an immuno-oncology therapeutic target to improve the efficacy of ICB.