The characterization of RUNX1-mediated macrophage polarization requires a multidimensional perspective beyond the M1/M2 binary.

We comment on the recent study by He et al. reporting that RUNX1 promotes non-small cell lung cancer (NSCLC) progression by driving a pro-tumoral macrophage program via the ACP5/β-catenin/SMAD3 axis, interpreted as "M2" polarization. While the M1/M2 framework (e.g., CD86 vs. CD206/Arg1) remains widely used, accumulating single-cell and spatial profiling data indicate that tumor-associated macrophages (TAMs) in vivo occupy a multidimensional continuum and may co-express canonical inflammatory and anti-inflammatory markers, challenging binary labeling. We propose that RUNX1 may induce a more specific TAM transcriptional program than a generic "M2" state and encourage future studies to apply high-resolution subtype annotations (e.g., SPP1 or C1QC TAM signatures) to define RUNX1-associated macrophage states more precisely. In addition, validating the RUNX1 axis in immunocompetent models (beyond NOD/SCID settings) and identifying tumor-derived upstream inducers (e.g., cytokines or exosomal cargos) would strengthen mechanistic completeness and translational relevance.