Chimeric antigen receptor (CAR) T cell therapy in solid tumors is hampered by dense stromal barriers, rapid functional exhaustion, and limited persistence. Here, we report that low-dose docetaxel acts as an immunomodulatory primer that reprograms CAR T cells to address these barriers. Retrospective analysis of breast cancer patients identifies host lymphocyte reserve as a key determinant of docetaxel treatment benefit, implying an immunological component beyond direct tumor cell killing.

Sub-cytotoxic docetaxel concentrations were evaluated in primary human T cells and CAR T cells using phenotypic, transcriptional, and functional assays. Secretory profiles and extracellular vesicle cargo were characterized, with efficacy assessed in 3D spheroids and xenograft models.

Docetaxel priming induces a "Metabolic-Cycle Uncoupling" state, constraining proliferation while enhancing cytotoxic effector potency and memory traits. This reprogramming is associated with upregulation of Rab27-dependent exosome biogenesis, accompanied by shedding of exhaustion markers (PD-1, CD57) and enrichment of cytotoxic ligands (FasL, TRAIL), CAR, and homing receptors (CCR5/CCR7). Primed CAR T cells exhibit improved antitumor efficacy with associated stromal remodeling and host T cell activation; secreted exosomes contribute to bystander tumor cell killing.

These findings describe a non-genetic pharmacologic priming strategy with potential scalability and compatibility with existing manufacturing processes. This approach demonstrates enhanced CAR T cell performance against solid tumor barriers in preclinical models, highlighting the potential of chemotherapy-immunotherapy synergies.

Low-dose docetaxel acts as an immunomodulatory primer that reprograms CAR T cells without impairing cellular viability. Sub-cytotoxic concentrations induce cell-cycle arrest with enhanced effector potency and memory traits, redirecting resources toward increased secretory activity. This promotes Rab27-dependent exosome biogenesis, with shedding of exhaustion markers (PD-1, CD57) and enrichment of cytotoxic ligands (FasL, TRAIL), CAR, and homing receptors (CCR5/CCR7). Primed CAR T cells exhibit improved antitumor efficacy with associated stromal remodeling and host T cell activation; secreted exosomes contribute to bystander tumor cell killing in spheroid and xenograft models.