Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.

Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

A growing body of evidence indicates that nonglycemic effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors play an important role in the protective effects of these drugs in diabetes, chronic kidney disease, and heart failure. In recent years, the anti-inflammatory potential of SGLT2 inhibitors has been actively studied. This review summarizes results of clinical and experimental studies on the anti-inflammatory activity of SGLT2 inhibitors, with a special focus on their effects on macrophages, key drivers of metabolic inflammation. In patients with type 2 diabetes, therapy with SGLT2 inhibitors reduces levels of inflammatory mediators. In diabetic and non-diabetic animal models, SGLT2 inhibitors control low-grade inflammation by suppressing inflammatory activation of tissue macrophages, recruitment of monocytes from the bloodstream, and macrophage polarization towards the M1 phenotype. The molecular mechanisms of the effects of SGLT2 inhibitors on macrophages include an attenuation of inflammasome activity and inhibition of the TLR4/NF-κB pathway, as well as modulation of other signaling pathways (AMPK, PI3K/Akt, ERK 1/2-MAPK, and JAKs/STAT). The review discusses the state-of-the-art concepts and prospects of further investigations that are needed to obtain a deeper insight into the mechanisms underlying the effects of SGLT2 inhibitors on the molecular, cellular, and physiological levels.

Background/Objectives: In gastric cancer, only a subset of patients benefit clinically from neoadjuvant chemoimmunotherapy, underscoring the need for robust biomarkers that can predict treatment responses and guide personalized immunotherapy. This study aimed to characterize the immune microenvironment of gastric tumors and identify predictive markers associated with therapeutic efficacy. Methods: We prospectively enrolled 16 patients with histologically confirmed, PD-L1–positive (CPS ≥ 1) gastric adenocarcinoma (T_2–4N_0–1M₀). All patients received eight cycles of FLOT chemotherapy combined with pembrolizumab. Treatment response was assessed by Mandard tumor regression grading. Spatial transcriptomic profiling (10x Genomics Visium) and multiplex immunofluorescence were used to evaluate tumor-infiltrating immune cell subsets and PD-1 expression at baseline and after treatment. Results: Transcriptomic analysis differentiated the immune landscapes of responders from non-responders. Responders exhibited elevated expression of IL1B, CXCL5, HMGB1, and IFNGR2, indicative of an inflamed tumor microenvironment and type I/II interferon signaling. In contrast, non-responders demonstrated upregulation of immunosuppressive genes such as LGALS3, IDO1, and CD55, along with enrichment in oxidative phosphorylation and antigen presentation pathways. Multiplex immunofluorescence confirmed a higher density of FoxP3⁺ regulatory T cells in non-responders (median 5.36% vs. 2.41%; p = 0.0032). Notably, PD-1⁺ CD8⁺ T cell and PD-1⁺ FoxP3⁺ Treg frequencies were significantly elevated in non-responders, suggesting that PD-1 expression within cytotoxic and regulatory compartments may contribute to immune evasion. No substantial differences were observed in PD-L1 CPS or PD-1⁺ B cells and PD-1⁺ macrophages. Conclusions: Our findings identify PD-1⁺ CD8⁺ T cells and PD-1⁺ FoxP3⁺ Tregs as potential biomarkers of resistance to neoadjuvant chemoimmunotherapy in gastric cancer. Transcriptional programs centered on IL1B/CXCL5 and LGALS3/IDO1 define distinct immune phenotypes that may guide future combination strategies targeting both effector and suppressive arms of the tumor immune response.

Colorectal cancer is the third most common cancer worldwide, making lymph node recovery critical for treatment decisions and prognosis. Within the colorectal tumor microenvironment, the metabolic programming of tumor-associated macrophages (TAMs) can drive both pro- and anti-tumor responses, yet the specific glycolytic pathways governing their pro-metastatic conversion present promising therapeutic targets. This study investigated the role of glycolysis activating enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in mediating TAMs metabolic polarization, and its potential as a therapeutic target. PFKFB3 expression was found to be predominant in TAMs in CRC tumor samples. Lipidomic analysis performed by HPLC-MS/MS revealed that PFKFB3 inhibition altered glycerophospholipid metabolism (p = 6.13 × 10⁻¹⁰), and shifted TAMs toward sphingolipid-mediated immunosuppressive metabolism. PFKFB3 activity was associated with a specific reduction in asparagine availability, potentially pointing to a targeted reprogramming of amino acid metabolism supporting distinct TAM functions under conditions of intra-tumoral metabolic stress. These findings highlight PFKFB3 as an essential regulator of TAMs pro-tumoral metabolism in CRC, particularly in colon cancer.

Type 2 diabetes mellitus (T2DM) is characterized by an uncontrolled increase in blood glucose levels and insulin resistance in cells of various tissues. Vascular complications in T2DM have an inflammatory nature. Drugs with different mechanisms of action have been developed and used to treat T2DM, initially aimed at controlling blood glucose levels. Among them, sodium-glucose cotransporter 2 inhibitors (SGLT2-i) were developed as specific inhibitors of glucose reabsorption in the kidneys, but along with lowering blood glucose levels, they demonstrated multiple (including non-glycemic) positive effects in the treatment of T2DM related to their beneficial effects on the immune system. SGLT2 inhibitors can reduce the risk of diabetic cardiomyopathy (DCM) and chronic kidney disease (CKD) development in patients with and without diabetes. SGLT2-is improve cardio-renal complications through a number of signaling pathways, including those dependent on the involvement of non-coding RNAs (ncRNAs) and their targets. The best-studied classes of ncRNAs are microRNAs, which are short (less than 200 bases) RNAs (miRNAs), long non-coding RNAs (lncRNAs) (more than 200 bases), and circular RNAs (circRNAs). The regulatory effect of ncRNAs has broad physiological significance, and changes in the ncRNAs’ expression are associated with the pathogenesis of different diseases, including T2DM. RNA-seq allows the construction of networks of interactions of lncRNA/circRNA-miRNA-mRNA called competitive endogenous RNA (ceRNA) networks, to identify clinically significant molecular markers, to improve the mechanistic understanding of pathogenesis, and to contribute to the development of new diagnostics and therapies. Our review summarizes the role of non-coding RNA in the action of SGLT2 inhibitors in cardio-renal complications in T2DM. We focus on methods of detection, genetics, and the effects of non-coding RNA. Specific attention is given to the role of non-coding RNAs in the inflammatory reactions of innate immune cells in relation to the SGLT2 inhibitors.