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Background Transforming growth factor-β (TGF-β) is a multifunctional cytokine that plays an important role in diverse physiological processes, including embryonic development, proliferation, differentiation, and immune responses. When TGF-β is overexpressed in the tumor microenvironment (TME), it interferes with the establishment of effective anti-tumor immune responses in a variety of ways, including by inhibiting the function of natural killer and CD8 + T cells. Therefore, inhibition of TGF-β is an attractive strategy to potentially increase the anti-tumor activity of immune-based therapies, including immune checkpoint blockade (ICB).Methods Due to the toxicities associated with systemic targeting of TGF-β, approaches to inhibit TGF-β activation locally at the tumor site are needed. Binding of the latent form of TGF-β to the integrins αvβ8 and αvβ1, which are expressed in tumor cells and cancer-associated fibroblasts, respectively, mediates the local activation of TGF-β in the TME. To investigate whether blockade of integrins could be used to increase responses to ICB, several murine models of cancer were evaluated for expression of the αvβ8 and αvβ1 integrin heterodimer subunits (αv, β1, β8). Tumors with the highest expression, including the triple negative EMT6 and the head and neck squamous carcinoma MOC1 models were selected for further analysis. Blockade of αvβ8 and αvβ1 integrins was achieved in vivo with the orally bioavailable, small molecule inhibitor PLN-101095, which was administered in the mouse chow.Results and Conclusions Scheduling assays demonstrated that PLN-101095 combined with anti-PD1 derived higher anti-tumor activity when PLN-101095 was administered prior to PD-1 blockade. In both models, the combination of PLN-101095 with anti-PD1 resulted in enhanced tumor control, which was associated with increased tumor infiltration with CD8 + T cells and increased frequency of IFNγ + and GzmB+ CD8+ T cells. In the EMT6 model, the combination therapy also significantly increased tumor infiltration with M1 macrophages and reduced the proportion of M2 macrophages, leading to decreased M2 to M1 macrophage ratio. In addition, EMT6 tumors treated with PLN-101095 and anti-PD1 showed a significant reduction in the amount of active TGF-β and Smad3 phosphorylation, indicating decreased TGF-β signaling in the TME. Furthermore, analysis of spleens of EMT6 tumor bearing mice treated with PLN-101095 monotherapy or the combination with anti-PD1 showed enhanced numbers of IFNγ + producing neoantigen-specific T cells, compared to the anti-PD1 and control groups. These data provided rationale for an ongoing, first-in-human phase I clinical trial (NCT06270706) of PLN-101095 in combination with pembrolizumab in solid cancers.