Transforming tumors into 'high-risk bombs' triggers a neoantigen storm and amplifies immune responses.

Although various immunotherapies have improved the treatment of several challenging malignancies in clinical applications, current research suggests that neoantigens remain fundamental to the initiation of immunotherapy, implying a dependence on high mutation loads in tumors and stable target antigens. To overcome these limitations, we propose a novel immunotherapy paradigm that interferes with splicing to induce the expression of neoantigens and neoepitopes while simultaneously blocking autophagy to prevent their degradation through endogenous pathways. This approach ensures the stable expression and accumulation of neoantigens and neoepitopes in tumor cells. To fully unleash the potential of neoantigens, we further induce tumors to undergo immunogenic cell death (ICD), triggering a "neoantigen storm" at the tumor site to recruit and activate more dendritic cells (DCs). Through a DC-dependent mechanism, communication between the tumor and the tumor-draining lymph node (TDLN) is enhanced, summoning more neoantigen-specific cytotoxic T lymphocytes to lyse tumor cells and establish immune circulation. In summary, this work presents a novel antigen-based immune sensitization strategy that stabilizes target antigens while exploring the potential of non-targeted antigens. By bypassing the cumbersome neoantigen identification process, this strategy holds promise for rapid clinical application in combination with other immunotherapies.