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Background Adoptive cellular therapy (ACT) in the form of CAR-T cell therapy has demonstrated potent clinical efficacy in hematological malignancies, however, its success in treating solid tumors has been very limited. The tyrosine phosphatases PTPN2 and PTPN1 negatively regulate several signaling pathways in immune and tumor cells. We previously demonstrated that oral administration of the PTPN2/N1 small molecule inhibitor ABBV-CLS-484 (AC484) promotes anti-tumor immunity in several syngeneic mouse tumor models and is now being explored in a Phase I clinical trial ( NCT04777994). ABBV-CLS-484 acts by both enhancing anti-tumor immune responses as well as in a cell intrinsic fashion by enhancing the susceptibility of tumor cells to immune-mediated killing. Considering this dual mechanism of action, we hypothesized that AC484 therapy would enhance CAR-T cell function and sensitize solid tumors to be more sensitive to ACT.Methods To test this hypothesis, we tested the ability of AC484 to enhance inhibition of tumor growth in syngeneic murine CAR-T and TCR ACT models to solid tumors. We also utilized RNA sequencing and flow cytometry to phenotype tumor-infiltrating immune and tumor cells post-treatment.Results AC484 treatment enhanced ACT efficacy to solid tumors. Consistent with these findings, immunophenotyping analyses demonstrated that in vivo AC484 therapy with CAR-T cells increased donor and endogenous T cell homeostatic proliferation, abundance, cytotoxicity, reprogrammed metabolism, persistence and reduced exhaustion. AC484 also enhanced IFNγ signaling in solid tumors to promote more ICAM, cytokine and chemokine expression to support T cell expansion and recruitment to the tumor.Conclusions Here, we describe a novel role for the PTPN2/PTPN1 inhibitor AC484 during adoptive cellular therapy. Our findings suggest that AC484 can positively impact both donor and endogenous T cells to eradicate solid tumors. We further show that AC484 treatment overcomes various common immune evasion mechanisms presented by solid tumors for successful ACT. These findings, along with our previous reports, underscore how AC484 significantly promotes anti-tumor efficacy through a multifaceted mechanism by sensitizing tumor cells to inflammation and enhancing the activity of a variety of immune subsets. These data suggest that AC484 therapy can be deployed in the clinic to markedly enhance adoptive T cell therapy for solid tumors.Acknowledgments C.H.P., I.S., Y.L., M.N.P., and J.D.P. are employees of Calico Life Sciences LLC. Q.Z., J.H., J.J.E, K.A.M., J.M.F, P.R.K, and C.K.B. are employees of AbbVie Inc.Ethics Approval Animals: All in vivo experiments conducted at AbbVie were in compliance with the NIH Guide for Care and Use of Laboratory Animals guidelines in a facility accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC). All in vivo studies conducted at Calico Life Sciences was approved by the respective IACUC committee.