The reciprocal modulation between the CXCL12/CXCR4/ACKR3 axis and the STAT3 signaling pathway plays a crucial role in the progression of various diseases and neoplasms. Activation of the CXCL12/CXCR4/ACKR3 axis triggers the STAT3 pathway through multiple mechanisms, while the STAT3 pathway also regulates the expression of CXCL12. This review offers a thorough and systematic analysis of the reciprocal regulatory mechanisms between the CXCL12/CXCR4/ACKR3 signaling axis and the STAT3 signaling pathway in the context of diseases, particularly tumors. It explores the potential clinical applications in tumor treatment, highlighting possible therapeutic targets and novel strategies for targeted tumor therapy.

The tumor secretome comprises the totality of protein factors secreted by various cell components within the tumor microenvironment, serving as the primary medium for signal transduction between tumor cells and between tumor cells and stromal cells. The deletion or mutation of the p53 gene leads to alterations in cellular secretion characteristics, contributing to the construction of the tumor microenvironment in a cell non-autonomous manner. This review discusses the critical roles of mutant p53 in regulating the tumor secretome to remodel the tumor microenvironment, drive tumor progression, and influence the plasticity of cancer-associated fibroblasts (CAFs) as well as the dynamics of tumor immunity by focusing on both secreted protein expression and secretion pathways. The aim is to provide new insights for targeted cancer therapies.

Introduction: Understanding the negative regulatory mechanisms of immune cell functions is essential for developing effective tumor immunotherapy strategies. Macrophages play a crucial role in antitumor immunity; however, the mechanisms that negatively regulate their antitumor functions remain incompletely understood. TIPE2 is known to be a critical regulator of various immune cells, but its role as a negative regulator of macrophage antitumor functions has not yet been established. Objectives: This study aims to investigate whether TIPE2 negatively regulates the antitumor functions of macrophages and to elucidate the mechanisms involved. Methods: We used a mouse model of hepatic tumor metastasis and a subcutaneous tumor model to evaluate the impact of TIPE2 on macrophage antitumor functions. In vitro experiments, including fluorescence microscopy and flow cytometry, were conducted to assess whether the TIPE2 deficiency enhances the phagocytic activity of macrophages against tumor cells. Additionally, we employed co-immunoprecipitation assays along with spleen tyrosine kinase (SYK) and Ras-related C3 botulinum toxin substrate 1 (RAC1) signaling blockade assays to investigate the molecular mechanisms through which TIPE2 exerts its negative regulatory effects. Results: Our findings indicate that TIPE2 gene loss in myeloid cells inhibits hepatic tumor metastasis, which is dependent on macrophages in the liver. Furthermore, macrophages lacking TIPE2 demonstrated enhanced tumor growth inhibition in subcutaneous tumor models. In vitro, these macrophages exhibited increased phagocytic activity against tumor cells. Mechanistically, TIPE2 negatively regulates the activation of SYK and RAC1, thereby modulating the phagocytic capabilities of macrophages. Conclusion: TIPE2 represents a negative regulatory mechanism for macrophage phagocytosis against tumor cells. In the future, TIPE2 may serve as a promising target to enhance the efficacy of tumor immunotherapy strategies based on macrophages.

Immune checkpoint blockade (ICB) has demonstrated efficacy in clinical cancer therapy; however, a significant proportion of cancer patients do not respond to ICB. One contributing factor to this lack of response is the impairment of IFN‐γ signaling within cancer cells. A20 acts as a negative regulator of IFN‐γ signaling. Our study aimed to investigate the mechanism by which A20 exerts its negative regulatory effect on IFN‐γ signaling in hepatocellular carcinoma (HCC) cells. Bioinformatic analysis revealed that A20 expression in HCC cell lines is inversely associated with the activation of IFN‐γ signaling. Functional loss and gain experiments demonstrated that A20 inhibits IFN‐γ signaling in HCC cells. The interaction between A20 and STAT1 was assessed using Co‐Immunoprecipitation (Co‐IP) assays and bimolecular fluorescence complementation (BioFC) assays. Our results also indicated that A20 suppresses the expression of downstream molecules involved in IFN‐γ signaling, such as CXCL9, CXCL10, and HLA‐ABC, in HCC cells. Additionally, enforced expression of A20 in HCC cells inhibited anti‐tumor immunity in a mouse model of HCC. Bioinformatic analysis suggests that A20 may negatively regulate IFN‐γ signaling in HCC cells from human HCC cohorts. Collectively, our study uncovers a novel mechanism whereby A20 inhibits IFN‐γ signaling in HCC cells through direct binding with STAT1. These findings enhance our understanding of the regulatory mechanisms of IFN‐γ signaling in cancer cells and provide insights for designing strategies to enhance the effectiveness of ICB therapy.