Abstract 2920: Metabolic reprogramming of hepatic macrophages restores CD8+ T cell immunity in T cell-desert hepatocellular carcinoma

Abstract CD8+ T cell-mediated immunosurveillance relies heavily on the functional integrity of antigen-presenting cells (APCs), particularly dendritic cells (DCs) that prime and activate T cells in secondary lymphoid organs. However, DCs are often defective in certain pathological contexts, such as β-catenin-mutated cancers, disrupting the cancer-immunity cycle and giving rise to “T cell-desert” tumor immunotypes that resist immunotherapy. Besides DCs, macrophages can also act as APCs and modulate CD8+ T cell activation, but their antigen-presenting function remains less well understood. Using genetic mouse models, we systematically characterized mice with macrophage-specific deletion of the mTORC1 suppressor Tsc1 and found a striking increase of CD8+ T cells in the liver-but not in other tissues. This tissue specificity likely reflects the unique intravascular niche in which Kupffer cells interact directly with circulating CD8+ T cells. Notably, this CD8+ T cell expansion occurs independently of DC compartments. In a MYC/β-catenin-driven “T cell-desert” hepatocellular carcinoma (HCC) model, TSC1-deficient hepatic macrophages (hMϕs) reinvigorated antigen-specific CD8+ T cell responses and suppressed HCC progression, also in a DC-independent manner. hMϕs from wild-type mice predominantly express T-cell immunoglobulin and mucin domain-containing 4 (TIM-4), while TSC1-deficient hMϕs consist of both TIM-4+ and TIM-4- subsets, with the TIM-4- population driving CD8+ T cell expansion. Moreover, TSC1-deficient hMϕs exhibited enhanced tumor antigen acquisition and presentation capacity. Combining TSC1 deficiency in hMϕs with anti-PD-L1 immunotherapy significantly improved outcomes in murine “T cell-desert” HCC. Metabolic profiling revealed markedly increased mitochondrial activity in TSC1-deficient hMϕs, and their enhanced APC and anti-tumor functions required malate-aspartate shuttle-mediated oxidative phosphorylation. Together, these preclinical studies reveal a DC-independent role for hMϕs in orchestrating CD8+ T cell immunity and suggest that metabolic reprogramming of macrophages may offer a promising strategy to overcome immune evasion in “T cell-desert” tumors caused by defective DC function. Citation Format: Liangliang Ji, Delaney Bessel, Sophia Brosnan, Isha Malik, Zijian Xu, Jiaxin Li, Peng Li, Xian Zhang, Jing Zhang, Ting-Wei Tsu, Shengyu Gao, Amaia Lujambio, Ming Li. Metabolic reprogramming of hepatic macrophages restores CD8+ T cell immunity in T cell-desert hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2920.