The IFN-γ response cycle: decoupling tumor killing from evolutionary selection in cancer immunotherapy

Interferon-γ (IFN-γ) confronts the field with an apparent contradiction that is better understood as a causal consequence: the cytokine most central to antitumor immunity is also a principal driver of immune escape, and recombinant IFN-γ has both helped and harmed patients. We argue that this duality is not paradoxical but expected, escape is, in large part, the predictable evolutionary outcome of effective IFN-γ–mediated pressure. The prevailing “two faces” framing, which separates antitumor and protumor effects by dose and duration, names this discrepancy without explaining what couples its halves. Here, we reframe IFN-γ as a time-ordered IFN-γ Response Cycle: a recurring causal motif, productive execution, a self-limiting turn, and selectable resistance, running around one tunable IFNGR–JAK–STAT1–IRF1 backbone. We use “cycle” deliberately and in a restricted sense: not to imply that an individual tumor clone oscillates between sensitive and resistant states, but that this execute–feedback–select motif recurs across a tumor’s heterogeneous clonal population and across successive rounds of immune pressure and therapy. Its reversible arc, adaptive feedback and non-genetic gating, can be therapeutically reopened, whereas genetic loss of the pathway constitutes a one-way exit from the cycle rather than a return within it. Its behavior is set less by signal magnitude than by decoding, which cells read the cytokine, at what intensity, in what spatial arrangement, and over what kinetics. Synthesizing evidence across tumor killing, antigen presentation, the cellular decoding network, adaptive and chronic feedback, genetic escape and induced phenotypic adaptation, therapeutic re-engineering, and biomarkers, we argue that resistance is largely manufactured by the very signaling that mediates control: by eliminating sensitive clones, IFN-γ selects for resistant clones. This recasts IFN-γ as a self-defeating selective force and reframes the therapeutic goal as decoupling killing from selection, preserving execution while severing the feedback and selection arc. IFN-γ biomarkers currently report the presence and dominance of an inflammatory, IFN-γ-driven state rather than a defined position within the cycle; longitudinal, spatial, and compartment-resolved measurements may eventually permit a finer classification.