Resetting the immune setpoint of cold tumors through a ferroptosis–cGAS–STING amplification circuit

Abstract Cold tumors remain a major challenge in cancer immunotherapy because of insufficient immune cell infiltration and limited inflammatory signaling, resulting in poor responses to immune checkpoint inhibitors. However, accumulating evidence suggests that many cold tumors are not completely immunologically inert but instead persist in a low-level immune state that fails to sustain effective immune amplification. Based on this perspective, we propose that cold tumors can be more appropriately understood as a threshold-constrained immune state, in which antitumor immune responses have been initiated but remain unable to surpass the immune activation threshold required to establish sustained immune amplification. Within this conceptual framework, we further propose a hierarchical model of immune dysfunction consisting of priming failure, trafficking failure, and penetration failure to explain the systemic mechanisms underlying immune resistance in cold tumors. Building upon this framework, we introduce the Ferroptosis–cGAS–STING amplification circuit as a conceptual model for driving immune state transition. In this model, ferroptosis activates the cGAS–STING–type I interferon axis through the release of tumor antigens and DNA-derived danger signals, whereas STING signaling, in turn, enhances cellular susceptibility to ferroptosis, thereby forming a transient amplification module constrained by temporal and metabolic conditions. This amplification module may enable subthreshold immune responses to overcome the immune activation threshold, thereby creating conditions for subsequent immune amplification while coordinately improving immune priming, immune cell recruitment, and tumor penetration, ultimately alleviating hierarchical immune barriers. Furthermore, we define the functional reprogramming of the tumor–immune system driven by crossing the immune activation threshold as immune setpoint resetting. We also discuss the key regulatory determinants and biological boundaries of this conceptual framework, including the temporal window of amplification, signal intensity, spatial constraints, and functional heterogeneity across different tumor contexts, together with its current limitations and future research directions. Overall, this review establishes a unified conceptual framework linking ferroptosis, innate immune activation, and immune remodeling in cold tumors, providing a systems-level perspective for understanding immune state transition and a theoretical foundation for designing immune interventions based on threshold crossing.