CD28 and cancer: In the future, exploring the antitumor efficacy of resistance to TME triggered by CD28 mutation strategies in the construction of ex vivo TME models that mimic the hypoxic, high-lactate, glucose-competitive, and immunosuppressive features of TME (101, 102) could further develop TME-induced enhanced CD28, or design response elements targeting the inhibitory signaling on the basis thereof, offering the possibility of CAR-T therapy for broader application to cancer and improved efficacy.