Longitudinal Imaging of the Premalignant Tumor Microenvironment Reveals Transient Myeloid States Predictive of Tumor Fate

The spontaneous regression of cancer lesions demonstrates the potential of immune surveillance; yet, these transient events have remained inaccessible to systematic study. Using longitudinal intravital microscopy in a carcinogen-induced model of head and neck cancer, we tracked premalignant lesions within the same animals for 24 weeks at single-cell resolution. This approach revealed three trajectories: progression, stability, or regression, and enabled dissection of the immune dynamics underlying each fate. Lesion outcome was dictated by the spatial organization of myeloid-derived antigen-presenting cells: regressing lesions were characterized by dense clusters of myeloid-derived cells associated with CXCL9 ⁺ /CXCL10 ⁺ expression and T cell recruitment, whereas progressing lesions displayed sparse, non-clustered infiltration. Remarkably, transient myeloid clusters arose prior to any detectable lesion formation and consistently marked regions that would later develop into premalignant lesions. These findings identify spatiotemporal myeloid organization as an early determinant of tumor fate and provide a mechanistic framework for predicting and intercepting cancer at its inception.