A Transcriptome-Inferred Binucleation State of CD10⁺ (MME⁺) Macrophages Consistent with Incomplete Cytokinesis: Morphology–Metabolism Coupling and a “Don’t-Eat-Me” Immune-Evasion Profile

Background: Binucleated and multinucleated macrophages (cells carrying two or more nuclei in one cell body) occur in granulomas and tumors, yet their origins beyond cell–cell fusion, and the macrophage role of CD10 (MME), remain unresolved. We asked who CD10⁺ macrophages are, whether their binucleation reflects incomplete cytokinesis (failure of the final separation step of cell division), and how this state relates to phagocytic immune evasion. Methods: Analyzing 20,000 lung adenocarcinoma myeloid cells (GSE131907), we applied a three-axis discrimination rule (molecular-output level, lineage concordance, G2/M activity), a six-module prediction model, and a 35-molecule eat-me/don’t-eat-me panel. Results: CD10⁺ cells comprised 16.2% of myeloid cells (87.6% C1QC⁺ tumor-associated macrophage (TAM)-derived, predominantly normal-lung-derived alveolar macrophages) and split by origin into scavenger and inflammatory–pro-angiogenic types (Type-1 and Type-2). Transcriptome-inferred binucleated candidates constituted 27.0% of CD10⁺ cells with G2/M programs directionally elevated (consistent with incomplete cytokinesis over fusion; attenuated after library-size control); the state and its key contrasts replicated in tumor-restricted cells and an independent NSCLC atlas. The lysosome module showed the largest association (unadjusted Δ = +0.222; persists after library-size control, residual Δ = +0.068); the classifier reached an AUC of 0.77 (same-cohort, not externally validated). These cells also showed a transcript-level shift of the don’t-eat-me/eat-me balance centered on CD47 (Δ = +0.127; calreticulin unchanged)—itself both an anti-phagocytic checkpoint and a multinucleation participant. Conclusions: We hypothesize that lysosomal stress drives cytokinesis failure and barrier co-assembly, nominating the CD10⁺ binucleated state as a testable node of phagocytic immune evasion for combination checkpoint targeting.