The M1 Paradox: Pro-Tumorigenic Effect of Macrophage Cytotoxicity in Prostate Cancer

Macrophages are highly plastic cells of the tumor microenvironment, and although classically activated M1 macrophages are generally regarded as anti-tumor effectors, their prolonged cytotoxic activity may also promote tumor adaptation. In this study, we investigated whether sustained exposure of prostate cancer cells to cytotoxic M1-like macrophages results in the selection of tumor cell populations with enhanced malignant properties. Macrophage-resistant derivatives of the human prostate cancer cell lines PC3 and DU145 were generated by repeated co-culture with cytotoxic THP-1-derived macrophages and characterized in vitro and in vivo. Macrophage-selected tumor cells showed increased proliferative activity and enhanced clonogenic survival. In vivo, these cells formed larger xenograft tumors with more aggressive histopathological features. At the same time, their migratory activity was not significantly increased, although they displayed partial epithelial-mesenchymal transition-like changes, including increased vimentin expression without a marked loss of epithelial markers. Transcriptomic profiling revealed coordinated inflammatory and adaptive reprogramming, characterized by the enrichment of cytokine- and immune-response pathways together with the suppression of metabolic and differentiation-associated programs. These changes were accompanied by the selective activation of p38 MAPK signaling, while sensitivity to paclitaxel remained unchanged. Taken together, the results indicate that macrophage cytotoxicity may act as a selective pressure promoting the emergence of inflammation-adapted tumor cell variants with increased malignant potential, supporting re-evaluation of the role of M1-like macrophages in tumor progression.