NK cells initiate an IFN-γ–dependent innate-to-adaptive immune cascade driving antitumor immunity upon ferroptosis induction
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Ferroptosis has been widely viewed as a downstream effector mechanism amplified by adaptive immunity. Here, we redefine ferroptosis as an immune-initiating event by demonstrating that GPX4 inhibition engages natural killer (NK) cells as essential upstream regulators. Mechanistically, early IFN-γ derived from NK cells provides a critical permissive signal that promotes dendritic cell maturation and primes subsequent CD8⁺ T cell responses, thereby establishing a functional innate–adaptive immune axis. Disruption of this NK cell–dependent circuit, such as in obese hosts, impairs ferroptosis-associated antitumor immunity and confers resistance to GPX4-targeted therapy. Notably, therapeutic activation of NK cells with IL-15 restores this immune–ferroptosis axis and overcomes treatment resistance. Together, our findings establish a cellular hierarchy in ferroptosis-associated immunity, identify NK cells as critical initiators of ferroptosis-driven antitumor responses, and provide a mechanistic rationale for combinatorial strategies to enhance ferroptosis-based cancer therapy.
