A shift from cytotoxicity to tissue remodeling immunotherapy for achieving cancer cure 3094

Abstract Description Cancer immunotherapies have significantly improved patient survival, yet achieving durable remission remains a major challenge due to tumors’ immune evasion mechanisms. This limitation reveals critical gaps in our understanding of immune surveillance and immunoediting, concepts primarily derived from infectious disease models that view immune responses as destructive. The widely accepted self-nonself (SNS) model reinforces this perspective, framing immune cells as destroyers of foreign pathogens while tolerating self-tissues. However, this view may miss essential immune functions beyond cytotoxicity. The integrity model suggests that immune cells preserve tissue integrity by suppressing autoreactive T cells. In contrast, the adaptation model posits that autoreactive immune cells play a key role in tissue homeostasis, even in malignancy. Disruptions in cellular stability can activate immune responses to restore tissue integrity and reshape the tumor microenvironment to inhibit tumor growth. Conventional immunotherapies, which focus on amplifying cytotoxic activity, may inadvertently worsen tissue disruption, fostering conditions that promote cancer progression despite temporary tumor shrinkage. By shifting from tumor eradication to immune-driven tissue homeostasis, this model offers a transformative approach. Here, we argue that future breakthroughs may lie in harnessing immune mechanisms that enhance tissue adaptability, providing a curative immunotherapy for cancer. Funding Sources This work was supported by funding from the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense. This work was also supported by P30 CA 016059. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)