Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with limited treatment options for advanced disease stages. Growing evidence implicates the gut microbiota in CRC pathogenesis, prompting interest in probiotics as a potential therapeutic strategy. In this study, we evaluated the effects of two probiotic compositions, CI (a mix of lactobacilli and bifidobacteria) and CII (bifidobacteria alone), in two murine CRC models: the orthotopic MC-38 cecum injection model and the inflammation-driven azoxymethane/dextran sodium sulfate (AOM/DSS) model. CI showed significant anti-tumor effects in the orthotopic model, reducing tumor weight and volume, which was, however, not associated with robust immune activation, suggesting microbiota-driven mechanisms. In contrast, CII was more effective in the AOM/DSS model, reducing colonic inflammation and completely preventing tumor development. Our study demonstrates that probiotics might have great therapeutic potential via modulation of the gut microbiota, and they can exert anti-tumor effects in murine models of CRC with distinct compositions showing differential efficacy depending on the model. CI stabilized the gut microbiome and inhibited pro-tumorigenic taxa in the MC-38 cecum injection model, while CII exhibited anti-inflammatory properties in the AOM/DSS model, highlighting the potential of probiotics as context-specific interventions for CRC. These findings contribute to the growing body of evidence supporting microbiota-targeted strategies in oncology and their relevance for therapeutic applications.

Tumor-associated macrophages (TAMs) in the colorectal cancer (CRC) microenvironment promote tumor progression but can be reprogrammed into a pro-inflammatory state with anti-cancer properties. Activation of the G protein-coupled receptor 84 (GPR84) is associated with pro-inflammatory macrophage polarization, making it a potential target for CRC therapy. This study evaluates the effects of the GPR84 agonists 6-OAU and ZQ-16 on macrophage activation and anti-cancer efficacy. GPR84 expression on THP-1 macrophages and murine BMDMs was analyzed using flow cytometry. Macrophages were treated with 6-OAU or ZQ-16, and pro-inflammatory cytokine levels, reactive oxygen species (ROS) production, and phagocytosis were assessed using qPCR and functional assays. Anti-cancer effects were tested in a subcutaneous MC38 tumor model, with oral or intraperitoneal agonist administration. Pharmacokinetics and compound stability were also evaluated. In THP-1 macrophages, 6-OAU increased pro-inflammatory cytokines and ROS production, with ZQ-16 showing similar effects. However, neither agonist induced pro-inflammatory responses, ROS production, or phagocytosis in murine macrophages. In vivo, both agonists failed to inhibit tumor growth in the MC38 model despite systemic exposure. Current GPR84 agonists lack efficacy in promoting anti-cancer macrophage activity, limiting their potential as CRC therapies.

Protein tyrosine phosphatases (PTPs) are key regulators of intracellular signaling cascades involved in cell growth, proliferation, differentiation, inflammation, and cancer. PTPN23, a non-receptor PTP, is involved in endosomal sorting and thereby regulates the internalization of growth factor receptors, such as the epidermal growth factor receptor (EGFR). PTPN23 has been proposed to exert tumor-suppressive effects in several epithelial cancers, including breast and lung cancer. PTPN23 is ubiquitously expressed in the body; however, it is particularly highly expressed in the intestine, where it plays an essential role in maintaining intestinal homeostasis. Despite these observations, its involvement in colorectal carcinoma (CRC) remains largely unexplored. To investigate the function of PTPN23 in CRC, we generated PTPN23-overexpressing CRC cell lines and evaluated their effects in vitro and in subcutaneous tumor models. Our in-vitro findings demonstrate that PTPN23 overexpression resulted in reduced proliferation levels and follow-up experiments showed suppression of colorectal cancer growth and proliferation in experimental CRC models. These effects were accompanied by changes in EGFR-associated signaling; however, the underlying mechanism, including a potential role of EGFR trafficking, remains to be established through direct experimental validation. Together, these findings expand current knowledge of PTPN23 in colorectal cancer and provide a basis for future studies addressing its biological function and therapeutic relevance.

T-cells are major therapeutic targets in cancer and immune-mediated diseases. Their development and differentiation require highly dynamic receptor turnover. Protein tyrosine phosphatase non-receptor type 23 (PTPN23) encodes a ubiquitously expressed pseudophosphatase involved in trafficking and internalization of specific cell receptors. Although PTPN23 has essential functions in several cell types, its role in T-cells remains unknown. We therefore investigated the role of PTPN23 in T-cells. We generated transgenic mice lacking PTPN23 specifically in T-cells (PTPN23-CD4-Cre). Flow cytometry, single-cell RNA sequencing (scRNA-seq), and proteomic analysis were performed in lymphoid and mucosal organs. PTPN23-CD4-Cre mice exhibited a significant reduction in total T-cell numbers in lymphoid organs, accompanied by increased proportions and numbers of γδ T-cells and markedly reduced naïve T-cells. Similar findings were made in mucosal organs, with γδ T-cell levels rising as age increased. In vitro functional assays revealed that residual PTPN23-CD4-Cre T-cells display an altered cytokine profile enriched for inflammatory mediators, a finding that was accompanied by proteomic and phosphoproteomic alterations consistent with changes in T-cell differentiation and inflammatory programs. scRNA-seq analysis showed altered representation of thymocytes along a shared developmental trajectory, with enrichment of PTPN23-deficient T-cells at earlier developmental states. Our study identifies PTPN23 as a previously unrecognized player of T-cell development, differentiation, and immune homeostasis.