Tumor-Associated Macrophages

Tumor-associated macrophages (TAMs) are central to tumor progression, immune suppression, and resistance to therapy, making them promising targets in cancer immunotherapy. TAMs exhibit functional heterogeneity, polarizing into pro-tumor (M2-like) and anti-tumor (M1-like) phenotypes under different microenvironmental cues. M2-like TAMs promote immune evasion, angiogenesis, and metastasis, while M1-like TAMs enhance antitumor immunity. Combining TAM-targeted therapies with immune checkpoint inhibitors is also emerging as a potential strategy to enhance immunotherapy efficacy. This review outlines TAM-mediated immunosuppression mechanisms, including the secretion of VEGF, TGF-β, and immune checkpoint molecules like PD-L1. We also summarize the current strategies targeting TAMs, such as blocking the CD47/SIRPα axis, using CD40 agonists, and PI3Kγ inhibitors, which have shown promise in preclinical studies. Overall, this review underscores TAMs as pivotal therapeutic targets and proposes future directions to optimize combinatorial immunotherapy for enhanced clinical outcomes.

Background: Glutathione peroxidase 4 (GPX4), an important factor regulating redox homeostasis, plays an important role in tumor microenvironment and progression. However, the role of GPX4 in gastric cancer (GC) is unclear. Methods: Spectral flow cytometry and multiplex immunohistochemistry were employed to assess the correlation between GPX4 expression and immune cell infiltration. Metabolomics analysis of conditioned media from GPX4 knockdown NUGC3 cells identified metabolic alterations. Additionally, both in vitro and in vivo functional studies were conducted to elucidate the mechanistic role of GPX4 in regulating the tumor microenvironment and progression. Results: Knockdown of GPX4 in GC cells inhibited tumor growth, enhanced CD8+ T cell infiltration, and suppressed the polarization of tumor-associated macrophages (TAMs) toward the pro-tumor M2 phenotype. Multiplex immunohistochemistry revealed a positive correlation between GPX4 expression and M2 macrophage infiltration in clinical samples from patients with GC. Metabolomics revealed that GPX4 knockdown regulate kynurenine metabolism pathway. Furthermore, mechanistic studies reveal that GPX4 silencing elevates lipid peroxidation, triggering the conversion of KYNU ubiquitin chain modifications from K48 to K63. Such ubiquitination remodeling stabilizes KYNU expression (a key kynurenine-metabolizing enzyme), reduces kynurenine accumulation, and ultimately reprograms TAM polarization to enhance antitumor immunity. We also identified that the K96 and K163 sites are important for KYNU's modification by K48 and K63 ubiquitin chains. Conclusion: Our study not only affirm the role of GPx4 in GC progression but also highlight it as a promising target for reshaping the immune microenvironment.

Glioblastoma (GBM) is an aggressive brain tumor with a highly immunosuppressive microenvironment that promotes tumor progression and therapy resistance. Tumor-associated macrophages (TAMs), comprising up to 50% of the tumor mass, are recruited via chemokine axes such as CCL2/CCR2, CX3CL1/CX3CR1, and CXCL12/CXCR4 and adopt an M2-like immunosuppressive phenotype, facilitating immune escape and angiogenesis. Key signaling pathways, including CSF1R, STAT3, NF-κB, PI3K/Akt, and HIF-1α, regulate TAM function, making them promising therapeutic targets. Strategies such as TAM depletion, reprogramming, and immune checkpoint blockade (PD-1/PD-L1, and CD47-SIRPα) have shown potential in preclinical models. Emerging approaches, including CAR-macrophage (CAR-M) therapy, nanotechnology-based drug delivery, and exosome-mediated modulation, offer new avenues for intervention. However, clinical translation remains challenging due to GBM's heterogeneity and adaptive resistance mechanisms. Future research should integrate multi-omics profiling and AI-driven drug discovery to refine TAM-targeted therapies and improve patient outcomes. This review provides a comprehensive analysis of TAM-mediated immune regulation in GBM and explores evolving therapeutic strategies aimed at overcoming its treatment barriers.

Tumor-associated macrophages (TAMs) predominantly exert functions that facilitate tumor progression. Triggering receptor expressed on myeloid cell 2 (TREM2) is expressed in TAMs, playing a crucial role in mediating the immunosuppressive function of TAMs. The mechanisms by which TREM2+ TAMs promote tumor growth and inhibit anti-tumor immunity remain unclear. Through single-cell sequencing of tumor tissues derived from wild-type and Trem2 knockout mice bearing subcutaneous lung cancer, it is found that TREM2 deletion hindered tumor growth, with a notable increase in and improved functionality of CD4+ T and natural killer (NK) cells in the tumor microenvironment. TREM2 deficiency led to ATP-binding cassette transporter A1 (ABCA1) downregulation, causing cholesterol accumulation in TAMs and promoting a pro-inflammatory phenotype. This results in increased chemokine (C-X3-C motif) ligand 1 (CX3CL1) secretion of macrophages, recruiting more CD4+ T and NK cells to the tumor site, enhancing the anti-tumor response. After screening food and drug administration (FDA)-approved drugs, bortezomib and ataluren are found to effectively inhibit TREM2 expression in TAMs, indicating a potential therapeutic strategy against TREM2. This study elucidates the mechanism by which TREM2 shapes the immunosuppressive microenvironment and promotes tumorigenesis, highlighting TREM2 as a target for cancer immunotherapy.