Tumor-DerivedHMGB1Orchestrates Lysosomal MetabolicReprogramming for M1 Macrophage Polarization

Abstract Non-small-cell lung cancer (NSCLC) is considered as a predominant contributor to cancer-related mortality with significant infiltration by TAMs. HMGB1 plays a key role in modulating immune evasion, but the mechanisms of HMGB1 in anti-NSCLC immunotherapy remain unclear. In this study, we first identified that cisplatin-resistant A549 CisR overexpresses HMGB1 and has hyperactivated autophagy, while cisplatin-sensitive A549 cells exhibit the opposite reaction. Using a HMGB1-targeted modulator, Naphplatin, we show that normalizing HMGB1 in both A549 and A549 CisR cell lines significantly triggers HMGB1-mediated inherent metabolic plasticity in tumors, thus releasing it to the thresholds required for macrophage activation. Mechanistically, in tumors, HMGB1 at threshold levels can effectively translocate to the cytoplasm from the nucleus, initiating lysosomal metabolism. Meanwhile, in macrophages, tumor-derived HMGB1 binds to RAGE, thereby promoting polarization toward the M1 macrophage phenotype. This study uncovers a divergent metabolic program mediated by HMGB1 and demonstrates its role in lysosomal metabolic plasticity.