JAK2 x STAT1 x STAT3

Tumor-associated macrophages depend on their amino acid metabolism to determine their properties and immune function and play important roles in the tumor microenvironment (TME). Although in previous studies, targeting amino acid metabolism to transform the protumor function of tumor-associated macrophages (TAMs) into antitumor immune function has shown promising application as a tumor therapy, current clinical research is still limited. There is a lack of discussion on the mechanism and treatment strategy for determining tumor progression by controlling amino acid metabolism in TAMs, as does a summary of studies on promoting tumor progression by reshaping amino acid metabolism in TAMs.

This review aims to systematically review and summarize the crosstalk between amino acid metabolism in TAMs and the TME, analyze the determining role of its metabolic network in tumor occurrence and development, and summarize therapies on this basis to help determine the development status and emerging technologies in the field of amino acid metabolism in TAMs for tumor therapy.

This review dissects how TAMs exploit amino acid dynamics via transporters, enzymes, and sensors to adopt protumoral phenotypes, depleting critical metabolites and crippling antitumor T-cell responses. We map the immunometabolic crosstalk through which TAMs reshape immunity, highlighting nutrient competition and metabolic byproducts as dual drivers of immune dysfunction. Emerging therapeutic strategies targeting these pathways (IFN-γ-JAK-STAT1 and IL-6/JAK2/STAT3) have been critically evaluated for their potential to reprogram TAMs and reverse immunosuppression. Key challenges, such as TAM heterogeneity, metabolic plasticity, and therapy resistance, are addressed, emphasizing the need for single-cell-resolution mapping of TAM metabolic states to identify context-dependent vulnerabilities. Finally, we advocate for combinatorial approaches that couple metabolic rewiring with immunotherapies, proposing that disrupting amino acid dependencies in TAMs could dismantle the immunosuppressive TME.

Although immune checkpoint inhibitors show great promise, not all patients respond, and many do not achieve durable responses. Consequently, further investigations into potentially targetable molecules that regulate immune checkpoints are warranted. Previous studies in several cancers demonstrated that interferons produced by tumor-infiltrating leukocytes regulate immunosuppressive PD-L1, PD-L2, and IDO1 through JAK/STAT signaling. Here, we investigated a novel role for an immunosuppressive environmental chemical receptor, previously implicated in smoking-related cancers, in IFN signaling in human lung adenocarcinoma (LUAD) cells. Deletion of the aryl hydrocarbon receptor (AhR) from A549 LUAD cells significantly decreased baseline JAK2, STAT1, STAT3, IRF1 (a JAK/STAT target), PD-L1, PD-L2, and IDO1 expression. IFNγ and IFNα increased the expression of JAK/STAT and immune checkpoint genes and proteins, but these increases were significantly diminished or absent in AhR-knockout cells. The AhR similarly controls IFN-induced, JAK/STAT-driven increases in multiple MHC class I- and class II-related genes. AhR control of type I and type II interferon signaling is mediated through up-regulation of an lncRNA, the IFN-stimulated non-coding RNA 1 (INCR1), and through repression of an RNA-binding protein, heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), which sequesters JAK/STAT-related and immune checkpoint gene transcripts. The data suggest that the AhR is a key mediator of tumor immunosuppression through regulation of IFN-induced INCR1 and JAK/STAT signaling and, thereby, expression of immune checkpoints. However, that immunosuppression may be tempered by AhR control of MHC expression. Given the multiple roles of JAK/STAT signaling in the immune system, the results also suggest multiple levels at which the AhR may affect tumor immunity.

Breast cancer remains the leading cause of cancer incidence and mortality among women worldwide, with triple-negative breast cancer (TNBC) posing significant treatment challenges. The dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway contributes to tumor progression, making it a potential therapeutic target. Chalcones, known for their diverse biological activities, including anti-cancer effects, hold promise for drug development. This study explores the anti-cancer activity of (E)-4-(3-(2-(benzyloxy)-6-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoic acid (chalcone-9), a novel chalcone derivative.

The cytotoxic effects of chalcone-9 were evaluated in breast cancer cell lines, including TNBC lines MDA-MB-231 and MDA-MB-468. Western blotting and qRT-PCR were used to analyze the impact on JAK1, JAK2, STAT1, and STAT3 activation and their downstream gene expression. In silico molecular docking analysis was conducted to determine whether chalcone-9 can interact with JAK1 and JAK2. A wound healing assay was used to observe the effect of chalcone-9 on tumor cell migration, and flow cytometry was employed to analyze whether chalcone-9 inhibits tumor cell cycle progression and induces apoptosis. The expression of apoptosis markers was also assessed.

Chalcone-9 exhibited dose-dependent cytotoxicity in breast cancer cell lines, with TNBC cells showing higher sensitivity. Chalcone-9 effectively inhibited the activation of JAK1, JAK2, STAT1, and STAT3, outperforming conventional JAK/STAT inhibitors. The structure of chalcone-9 was confirmed to stably interact with JAK1 and JAK2 proteins. It also suppressed STAT1 and STAT3 target gene expression, reduced tumor cell migration, and induced apoptosis, as evidenced by PARP and caspase cleavage and decreased survivin levels.

Chalcone-9 demonstrates significant anti-cancer activity, particularly against TNBC. By targeting the JAK/STAT pathway and promoting apoptosis, chalcone-9 emerges as a promising therapeutic candidate for aggressive breast cancers.