<p>CAR-T cell therapy has shown great success in hematological malignancies. However, this immunotherapeutic strategy faces critical challenges in solid tumors mainly due to the key hurdles brought about by the hostile tumor microenvironment (TME). Effective CAR-T cell therapy in solid tumors is hampered by low tumor infiltration of the administered T cells due to the dense fibrotic nature of the TME and its aberrant vasculature. Also, solid tumors shape a highly immunosuppressive milieu in which the cytotoxic activity and persistence of functional CAR-T cells are abolished. Trefoil factor family (TFF) peptides, especially TFF3, have recently drawn a lot of attention due to their pro-tumor activities. Based on the recent evidence, TFF3 is upregulated in solid tumors where it plays roles in chemotherapy resistance, increased survival, and proliferation of cancer cells, expansion of the immunosuppressive cells and enhanced angiogenesis, which contributes to the aberrant tumor vasculature. In this review, we explore how TFF3 signaling contributes to tumor progression and immune escape, and how its inhibition might reshape the tumor microenvironment (TME) to better support CAR-T cell activity. Mounting evidence suggests that blocking TFF3 could help reduce immunosuppression, restore more normal blood vessel structure, and disrupt the pro-fibrotic and tumor-promoting interactions driven by cancer stem cells (CSCs). At the same time, since TFF3 plays an important role in protecting mucosal tissues and promoting repair after injury, its inhibition needs to be approached carefully. We also discuss strategies to selectively block TFF3 within tumors while minimizing unwanted effects on healthy tissues. Gaining a deeper understanding of how TFF3 contributes to therapy resistance may open up new opportunities to enhance CAR-T cell treatment in solid tumors, either through combination therapies or as a preconditioning step before CAR-T cell infusion.</p>