Interferon-induced transmembrane (IFITM) proteins at the tumour-immune interface: A four-axis framework for their context-dependent roles.

BACKGROUND: The interferon-induced transmembrane (IFITM) protein family, including IFITM1, IFITM2, IFITM3, and the less-characterized IFITM5 and IFITM10, has emerged as a recurrent yet mechanistically complex group of players in cancer, reported as oncogenic in one setting and tumor-restraining in another, immunosensitizing in one context and immunotherapy-resistance-promoting in the next. Rather than treating this literature as contradictory, we argue it is unresolved, and we organize it around a four-axis framework defined by the interaction of member identity, interferon (IFN)-input quality, cellular compartment, and tumor milieu. MAIN BODY: We first establish the foundational biology that compels this framework: family members are not interchangeable, occupying distinct subcellular compartments and partner networks; their abundance is set jointly by upstream IFN signaling and tumor-cell-intrinsic regulators; and post-translational state gates their function independently of expression. We then refine the prevailing view of IFN signaling as monolithic, reformulating the direction of IFITM functional output around an acute-versus-chronic IFN distinction in which transient signaling drives major histocompatibility complex class I (MHC-I) induction, antigen presentation, and immunogenicity, whereas sustained signaling promotes programmed death-ligand 1 (PD-L1)-coupled adaptive immune resistance and engagement of the interferon-stimulated gene resistance signature (ISG.RS). Surveying tumor-cell-intrinsic, immune-cell-intrinsic, stromal, and microbiota-conditioned compartments across diverse malignancies, we show that the sign of any IFITM effect is set by where, when, and which member is expressed. The field's most prominent conflicts are reframed as falsifiable hypotheses with defined discriminating experiments. CONCLUSION: We conclude that translational maturity remains limited to biomarker discovery, and that compartment-resolved, IFN-quality-stratified, immune-competent studies, not further expression surveys, are the necessary next step. KEY POINTS: Member, IFN quality, compartment, and milieu define IFITM cancer effects. IFITM paralogs engage distinct signaling networks across tumor and immune cells. Acute IFN favors MHC-I immunogenicity; chronic IFN drives PD-L1 resistance. Context resolves opposing IFITM effects into experimentally testable predictions. Near-term translation favors biomarker stratification over direct IFITM targeting.