To enhance therapeutic outcomes, strategic approaches can be prioritized, such as optimizing co-stimulatory signals in CAR-T cells (e.g., combining CD28 and 4-1BB domains), improving the tumor microenvironment (e.g., immunosuppressive cell depletion, physical barrier disruption, hypoxia and metabolic stress alleviation), and exploring novel dual CAR-T cell designs (e.g., logic-gated CARs) to address antigen heterogeneity and enhance persistence 11, 28, 154, 155. Here, CD28 is linked to neoplasm.