Initial tumor infiltration leads to differentiation into activated, functional CD8 + T cells, more recently described as progenitor-exhausted T cells ( 5, 6). Exhausted T cells are defined by expression of multiple coinhibitory receptors such as PD-1, TIM-3, and LAG-3, as well as progressive loss of proliferative potential and effector cytokine production, ultimately leading to failed antitumoral responses ( 4, 5). One limitation of immunotherapy in solid tumors is tumor microenvironment–induced T cell exhaustion, a terminally differentiated T cell state driven by chronic T cell activation and tumor microenvironment factors ( 3). ![]() Current immunotherapeutic modalities, including enhancing endogenous tumor-infiltrating lymphocytes (TILs) by checkpoint blockade or adoptive transfer of chimeric antigen receptor–modified (CAR-modified) autologous T cells into patients, show evidence of sustained cancer remission or clearance in some patients, but overall response rates remain low, especially in advanced solid tumors ( 1, 2). Immunotherapy is evolving rapidly to provide new strategies for the treatment of cancer. Thus, HIF activity in CD8 + TILs promotes accumulation and antitumor activity, providing a new strategy to enhance the efficacy of ACTs. VHL deficiency similarly facilitated enhanced accumulation of chimeric antigen receptor (CAR) T cells with a Trm-like phenotype in tumors. VHL-deficient TILs accumulated in tumors and exhibited a core Trm signature despite an exhaustion-associated phenotype, which led to retained polyfunctionality and response to αPD-1 immunotherapy, resulting in tumor eradication and protective tissue-resident memory. Here, we report that deletion of the HIF negative regulator von Hippel-Lindau (VHL) in CD8 + T cells induced HIF-1α/HIF-2α–dependent differentiation of tissue-resident memory–like (Trm-like) TILs in mouse models of malignancy. ![]() Promoting CD8 + T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. ![]() Adoptive T cell therapies (ACTs) hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of this cellular immunotherapy approach.
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