CD28 and colorectal carcinoma: The CD28 costimulatory domain is known to facilitate robust initial T-cell activation and proliferation, whereas 4-1BB (CD137) costimulation is associated with enhanced T-cell longevity and sustained antitumor activity, which are attributed to improved mitochondrial biogenesis and metabolic fitness.117,118 In the context of solid tumors, where long-term T-cell persistence and resilience against the immunosuppressive TME are crucial, 4-1BB may confer significant advantages by augmenting resistance to inhibitory factors prevalent in CRC.