Dual CD40/CD28 co-stimulation reprograms the solid-tumor microenvironment to unleash CAR-T and endogenous anti-tumor immunity

LACO-CAR-T, combining CD40 and CD28 signaling via LACO-Stim, achieved durable complete tumor regression in most mice, outperforming transient control in xenograft and immunocompetent models.

• Why it matters: Solid tumors limit CAR-T efficacy through poor persistence, an immunosuppressive TME, and immune evasion, leaving a need for strategies that remodel both T cells and the surrounding myeloid landscape.
• What they did: The authors engineered LACO-Stim, a single chimeric co-stimulatory molecule delivering CD28 signaling to the bearing T cell while activating CD40-expressing antigen-presenting cells, then tested it with a 4-1BB-based CAR in vitro and in mouse tumor models.
• The result: In immunocompetent hosts, LACO-CAR-T activated dendritic cells, shifted tumor macrophages toward M1-like antigen-presenting states, induced epitope spreading with endogenous CD8 responses to neoantigens, and synergized with anti-PD-1 blockade to control tumor growth.

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