TLR9 Agonists Potentiate Adoptive T Cell Therapy in Cancer through a B Cell–CD2 Costimulatory Axis

Adoptive T cell transfer (ACT) therapy offers curative potential for some patients with cancer. Toll-like receptor (TLR) agonists improve the efficacy of ACT therapy, but the underlying mechanism of potency remains poorly understood. Here, we identify a previously unrecognized innate-adaptive circuit in which TLR9-activated B cells augment CD8 T cell fitness and antitumor activity through CD2-dependent costimulation. Among multiple TLR agonist tested, class B CpG uniquely programmed murine and human CD8⁺ T cells for superior effector differentiation, metabolic fitness and antitumor control. Disruption of CD2 signaling blunts the benefits of TLR9 agonism, including glycolytic capacity and tumor control. Independently, blocking CD86/CD80/CD28 or ICOS did not impair CpG conditioned CD8 T cell anti-tumor activity. Gain of function experiments revealed that CD2 stimulation recapitulated the effect of TLR9 agonism, bolstering the effector function of TIL and CAR T cells. Clinically, consistent with these findings, elevated CD2 expression in human tumors correlated with improved overall survival across multiple cancer cohorts, underscoring the importance of this signaling cue. Together, these data uncover a non-canonical B cell-CD2 costimulation axis through which TLR9 agonists potentiate ACT, revealing a targetable pathway to overcome resistance to cell therapy in solid tumors.