From a therapeutic perspective, mechanism driven combination strategies should be tailored according to differentiation hierarchy: DTC: immune activation approaches based on antigen presentation and T cells restoration (such as cancer vaccines or local radiotherapy combined with PD-1 blockade) (125, 126); PDTC: myeloid reprogramming combined with multi-checkpoint inhibition (53); ATC: highest potential for combinatorial immunotherapy, emphasizing anti-exhaustion strategies, STING pathway activation, and stromal unlocking NK cells reactivation (127–129). This evidence concerns the gene STING1 and cancer.