Macrophage barrier responses to oncogenic transformation

The well-documented protumorigenic roles of macrophages in advanced cancers can sometimes overshadow their beneficial functions in the earlier stages of tumor development. This essay explores the hypothesis that macrophages play a crucial protective role in premalignant tissues by sensing and responding to early oncogenic transformation. Their activity is closely intertwined with cell-intrinsic barriers to transformation — such as apoptosis, senescence, and DNA repair — which collectively work to suppress malignant progression. Thus, an integrated cell-intrinsic and macrophage response constitutes effective ‘oncogenic monitoring’. In premalignant tissues, macrophages interpret outputs of cell-intrinsic tumor suppression as oncogenic stress signals detected through innate immune sensors, initiating a protective, homeostatic response that mitigates potential progression to malignancy. By recontextualizing macrophage roles in the early immune landscape, it becomes evident that these cells can serve as key protectors, preventing or delaying tumor formation. Understanding this dual role of macrophages — protective in early tumorigenesis and protumorigenic in established cancers — offers new perspectives on harnessing their immune functions for cancer prevention and therapy.