Upregulation of macrophage UPP1 promotes lung adenocarcinoma metastasis through an mtROS-cGAS-NLRP3 inflammasome axis.

Tumor-Derived HMGB1 Orchestrates Lysosomal Metabolic Reprogramming for M1 Macrophage Polarization

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.

Tumor‐Derived Exosomal circAP2B1 Induces M2 Macrophage Polarization by Enhancing Mitochondrial Homeostasis to Promote Esophageal Squamous Cell Carcinoma Progression

ABSTRACT Esophageal squamous cell carcinoma (ESCC) remodels the immunosuppressive tumor microenvironment via exosome‐mediated intercellular communication. In this study, circular RNA circAP2B1 is identified as a critical regulatory molecule that is markedly upregulated in ESCC tissues and patient serum and strongly associated with poor prognosis. Mechanistically, tumor‐derived exosomes efficiently deliver circAP2B1 to tumor‐associated macrophages (TAMs), where it serves as a distinct molecular scaffold that simultaneously binds the transcription factor ESRRA and the nuclear import receptor KPNA1, facilitating ternary complex formation and ESRRA nuclear translocation. Once in the nucleus, ESRRA directly activates the transcription of Mitofusin 2 (MFN2), a pivotal regulator of mitochondrial fusion, thereby enhancing mitochondrial oxidative phosphorylation, improving ATP production efficiency, and establishing a metabolically optimized intracellular environment that ultimately drives TAMs toward a pro‐tumor M2 phenotype. Both in vitro and in vivo experiments demonstrate that targeted intervention of the circAP2B1/ESRRA/KPNA1/MFN2 signaling axis effectively reverses M2 polarization and markedly suppresses tumor progression. This study uncovers a novel exosomal circRNA‐mediated metabolic‐immune regulatory pathway and offers new avenues for the diagnosis and treatment of ESCC. The findings not only expand the understanding of circRNA functions in tumor immunity but also provide a theoretical basis for the development of therapies targeting the metabolic‐immune axis.

MARCKS Drives Immunosuppressive Signaling in Tumor-Associated Macrophages to Promote Lung Cancer Progression 2258297

Lung cancer is the deadliest pulmonary malignancy, driven in part by immune evasion and limited treatment options. Among key immunoregulatory players, tumor-associated macrophages (TAMs) promote angiogenesis, immunosuppression, and metastasis via M2-like polarization. MARCKS (myristoylated alanine-rich C-kinase substrate), an oncogenic regulator, is highly expressed in both tumor cells and TAMs, with elevated levels linked to cancer progression. However, its role in TAM-mediated immune modulation remains poorly understood. We analyzed single-cell RNA sequencing data from lung cancer patients. TAMs were stratified into MARCKS-proficient (MARCKS+) and -deficient (MARCKS⁻) subsets. Differential expression and pathway enrichment analyses were performed, and CellChat was used to assess intercellular communication. MARCKS+ TAMs were enriched for immunosuppressive pathways, including IL-10 family cytokines, efferocytosis, and CD163-associated M2 programs. CCR5-related pathways implicated proliferative and migratory signaling, while suppression of T cell immunity suggested immune evasion. CellChat analysis showed significantly increased communication by MARCKS+ TAMs. Key outgoing ligands included SPP1, CCL, MIF, VEGF, TNF, and TGF-β, whereas incoming signals featured TGF-β, TNF, ITGB2, and SPP1. MARCKS+ TAMs uniquely received TGF-β, a potent M2 inducer, and secreted SPP1, linked to metastasis, therapy resistance, and fibroblast differentiation into cancer-associated fibroblasts. MIF—CD74—CXCR4 signaling further contributed to Treg recruitment and NK cell suppression. MARCKS+ TAMs amplify immunosuppressive signaling that enhances macrophage polarization, immune evasion, and tumor-stromal crosstalk. By driving TGF-β- and SPP1-mediated interactions with tumor and immune compartments, MARCKS emerges as a key regulator of TAM-driven immunosuppression and a potential therapeutic target in lung cancer. This work was supported by the NIH grant R01HL146802, the UCOP TRDRP grant T32IR5347, and the DoD PRMRP grant W81XWH2110086 (#PR202411). Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

TREM2 mediates macrophage suppression of NLRP3 inflammasome pathway to promote non-small cell lung cancer progression

M2 macrophage-derived exosomal EHF transcriptionally activates FGFR1 to promote malignant phenotypes and glycolysis in NSCLC

FADS1-mediated Efferocytosis in Tumor-Associated Macrophages Shapes an Immunosuppressive Microenvironment in Gastric Cancer.

Tumor-associated macrophages (TAMs) play a central role in tumor progression and therapeutic resistance. Alterations in unsaturated fatty acids (UFAs) metabolism are known to contribute to the immunosuppressive properties of TAMs. However, the complex regulatory relationship between UFAs metabolism and TAMs during gastric cancer (GC) progression remains largely unclear. Through a comprehensive analysis of single-cell RNA sequencing and transcriptomic data, we found that the UFAs biosynthesis-related enzyme FADS1 holds prognostic significance in GC within TAMs. Clinically, a high infiltration of FADS1+TAMs strongly correlates with poor prognosis and immunotherapy resistance across several GC cohorts. Using in vitro co-culture systems and in vivo mouse models, our data suggest that FADS1+TAMs actively contribute to an immunosuppressive microenvironment, potentially driving CD8+T cell dysfunction. Mechanistically, our findings indicate that FADS1 mediated DHA synthesis and activated PPARγ, which subsequently promotes efferocytosis and inhibit the STING-IFN-I signaling pathway in TAMs. Notably, systemic pharmacological targeting of FADS1 exerted a significant sensitizing effect in mouse ectopic GC models, inhibiting tumor growth, enhancing CD8+T cells cytotoxicity, and improving the efficacy of PD-1 blockade. Overall, our study highlights FADS1+TAMs as a critical component of GC progression and a potential exploratory biomarker for immunotherapy responsiveness. Furthermore, pharmacological inhibition of FADS1 represents a promising combinatorial strategy for reshaping the TME and enhancing immune checkpoint blockade efficacy in preclinical settings.