Moving beyond cytotoxicity in cancer immunotherapy: embracing tumor microenvironment remodeling for durable control

The quest for a curative cancer immunotherapy remains elusive, hindered by a longstanding focus on tumor cell elimination through cytotoxic mechanisms. However, mounting evidence points to an underappreciated dimension of immune function: its capacity for tissue remodeling and homeostasis, which can shape a tumor-inhibitory microenvironment. This perspective review highlights the adaptation model of immunity, which reframes the immune response as a dual force capable of both preserving and disrupting tissue integrity. Central to this model is Signal IV, a novel pathway in which self-reactive immune cells interact with adaptation receptors (AdRs) on tissue cells through adaptation ligands (AdLs) on immune cells. This interaction activates anti-apoptotic pathways in target cells, enabling immune responses to promote tissue survival and homeostasis even in the presence of cytotoxic mediators. Crucially, the downregulation of AdRs in stromal cells, while preserved in malignant cells, creates a tumor-promoting microenvironment, whereas the reverse fosters tumor rejection. This paradigm challenges conventional approaches by shifting the focus from tumor cell destruction to restoring tissue integrity, offering a revolutionary framework for immunotherapy. By targeting the AdR-AdL axis to reprogram the tumor microenvironment, the adaptation model proposes a transformative strategy for harnessing immune responses to achieve durable cancer control.