Qianyu Li

Hepatocellular carcinoma (HCC) driven by gain-of-function mutations in CTNNB1 (CTNNB1GOF) that stabilize β-catenin exhibits a profoundly immunosuppressive tumor microenvironment (TME), rendering it resistant to immune checkpoint blockade (ICB). Metabolic reprogramming is increasingly recognized as a crucial mediator of immune activity, highlighting the need to elucidate the specific metabolic mechanisms underlying immune exclusion in CTNNB1GOF HCC. In this study, we identified a critical metabolic–immune network orchestrated by comutations of CTNNB1 and ARID2. Integrative analysis of cohorts of patients with HCC and a de novo MYC/CTNNB1GOF HCC mouse model revealed that tumors harboring concurrent CTNNB1 and ARID2 mutations exhibited a more immune-active TME and improved survival compared with tumors with CTNNB1 mutations alone. Mechanistically, β-catenin and ARID2 cooperatively enhanced the transcription of tryptophan 2,3-dioxygenase (TDO2), leading to accelerated kynurenine production and activation of the aryl hydrocarbon receptor (AhR) in myeloid-derived suppressor cells (MDSC). This metabolic axis established an immunosuppressive milieu characterized by MDSC accumulation and impaired T-cell function. Genetic ablation of Arid2 in CTNNB1GOF HCC attenuated TDO2-dependent kynurenine synthesis, reduced MDSC infiltration, and enhanced CD8+ T-cell cytotoxicity, thereby sensitizing tumors to anti–PD-1 therapy. Clinically, comutations of CTNNB1 and ARID2 correlated with elevated immune infiltration and favorable ICB responses across multiple human cancers, including HCC. Importantly, pharmacologic inhibition of AhR phenocopied the immunomodulatory effect of ARID2 loss and, when combined with anti–PD-1, robustly reversed the immune-cold phenotype of CTNNB1GOF HCC. These findings reveal TDO2–kynurenine–AhR signaling as a pivotal metabolic pathway enforcing immune evasion in CTNNB1-mutant HCC. Significance: β-catenin and ARID2 cooperatively orchestrate a metabolic immunosuppressive program in hepatocellular carcinoma by driving kynurenine production and AhR activation, identifying AhR inhibition as a promising therapeutic strategy to enhance immunotherapy efficacy.

How intracellular proteins, normally hidden from the immune system, become targets of tumor-associated antibody responses remains unresolved, as does the function of such autoantibodies encoded by tumor-infiltrating B cells (TIL-Bs). Using monoclonal antibodies (mAbs) cloned from TIL-Bs in a spontaneous hepatocellular carcinoma (HCC) model, we define a class of antigens: secreted intracellular antigens (SICAs). Tumors co-opt upregulated autophagy to release cytosolic proteins, exemplified by ALDH1L1, through HSP90-mediated autophagy-dependent unconventional secretion. The resulting autoantibodies form immune complexes at the tumor site, where the SICA is locally available, recruiting and reprogramming neutrophils into tumor-associated neutrophils that drive tumor progression. Both neutrophil depletion and loss of Fcγ receptor binding abolish this effect. Autophagy-mediated SICA secretion and the corresponding autoantibody response are conserved in HCC patients and extend to lung, breast and cervical cancers. Tumors thus reshape their secretome to hijack humoral immunity, highlighting the SICA–autoantibody–FcγR axis as a potential therapeutic target.