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Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation. We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitr o and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model. Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype. Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice. BTKIs attenuate T-cell and CART19 exhaustion mediated by sustained TCR stimulation and CAR tonic signaling and impede release of IL-6 and TNF-α by macrophages. In addition, BTKIs reprogram macrophages toward the M1 subtype and polarize Th cells to the Th1 subtype in the tumor micro-environment. Image was created with BioRender.com. BTKIs, Bruton tyrosine kinase inhibitors; CAR, chimeric antigen receptor; CART19, anti-CD19 chimeric antigen receptor T-cell; IL-6, interleukin 6; TCR, T-cell receptor; Th, T helper; TNF-α, tumor necrosis factor alpha. [Display omitted] [ABSTRACT FROM AUTHOR]