DEA hypothesis: disinhibition, enhancing recognition, and alerting the host are the three pillars of effective cancer immunotherapy

Why are clonal neoantigens paradoxically rare in established tumors? Why does tumor-associated antigen (TAA) burden inversely correlate with T-cell infiltration? Why do damage-associated molecular pattern (DAMP)/danger signal-inducing interventions (messenger RNA (mRNA) vaccines, stereotactic body radiotherapy (SBRT), immunogenic chemotherapy) enhance checkpoint blockade activity in “cold” tumors? We propose the “DEA Hypothesis” to resolve these paradoxes: durable antitumor immunity for established tumors requires three convergent signals—(1) D isinhibition of T cells through checkpoint blockade, (2) E nhanced recognition via the presentation of clonal neoantigens, and crucially, (3) A lerting the host through release of DAMPs/danger signal(s). We frame cancer as a subversion of an ancient “Guardian” system—the emergency hematopoietic response that evolved to orchestrate immune defense following epithelial breach or major trauma. Tumors hijack this system by promoting restorative hematopoiesis at the expense of immunity and masquerading as chronic wounds. This framework explains key observations: the paucity of clonal neoantigens reflects successful immunoediting over years of tumor evolution, not failed presentation. TAAs persist in cold tumors because insufficient DAMPs limit the “Decision to Attack”; and mRNA vaccines, recently SBRT, and immunogenic chemotherapy succeed in cold tumors by providing the missing Alert. For cold tumors, rational immunotherapy must extend beyond checkpoint blockade to reconstitute the Alert signal—not merely releasing the brakes but providing the ignition to reawaken the ancient Guardian.

Graphic abstract: The DEA hypothesis proposes that effective cancer immunotherapy requires three convergent signals: Disinhibition (checkpoint blockade), Enhanced recognition (clonal neoantigens), and Alerting the host (DAMP release). Panel I depicts immune decision points in tumor-draining lymph nodes. Panel II shows mutation-driven DAMP generation via the Poly(ADP-Ribose) Polymerase 1 - High Mobility Group Box 1 (PARP1-HMGB1) axis. Panel III illustrates the three-signal model converging on type 1 conventional dendritic cells activation. Panel IV demonstrates how immunoediting shapes stage-specific therapeutic strategies for cold, warm, and hot tumors.