CAR T cells, which activate the immune system, have revolutionised the treatment of hematological cancers. However, the immunosuppressive tumor microenvironment (TME) in solid tumours presents significant challenges by preventing T cell infiltration, activation, and cytotoxicity following antigen recognition. These barriers substantially limit the efficacy of CAR T cells against solid tumours, necessitating innovative strategies to improve treatment outcomes. Our team has been at the forefront of advancing CAR T cell technology, focusing on targeting the Lewis Y (LeY) tumour-associated antigen in prostate cancer. We have adopted a multifaceted approach to enhance CAR T cell infiltration and persistence in patient-derived xenograft (PDX) models of prostate cancer. Initially, we employed chemotherapy to modify the TME composition. Mechanistically, this strategy involved altering the phenotype of cancer-associated fibroblasts, remodelling the vasculature, promoting extracellular matrix degradation, and reprogramming macrophage differentiation toward the pro-inflammatory M1 phenotype. Together, these changes established a pro-inflammatory TME that supported both early and sustained CAR T cell infiltration. Building on this foundation, we developed next-generation CAR T cells directed against LeY, incorporating the memory-associated transcription factor FOXO1. Our data demonstrate that FOXO1-LeY CAR T cells significantly enhance tumour regression, particularly in less sensitive PDX models. Notably, when combined with the pro-inflammatory TME changes induced by low-dose carboplatin, these CAR T cells exhibited superior efficacy. This approach has proven especially promising in models of neuroendocrine prostate cancer, a highly aggressive subtype with limited treatment options. Future efforts will focus on further optimising the combination of TME-modulating agents and advanced CAR T cell constructs. These studies represent a critical step toward developing effective immunotherapeutic options for patients with LeY-positive, treatment-resistant prostate cancers.