Colorectal cancer remains one of the leading causes of cancer-related mortality worldwide, largely due to metastasis and limited responses to immunotherapy in most patients. Although immune checkpoint inhibitors have transformed treatment for certain tumor subtypes, the majority of colorectal cancers remain "immune-cold," meaning they fail to trigger effective anti-tumor immunity. Increasing evidence suggests that tumor-associated macrophages, especially the M2 subtype, actively promote tumor growth, invasion, and immune suppression. However, the molecular signals that drive macrophage polarization within colorectal tumors remain poorly understood. Understanding how tumor cells reshape immune behavior is therefore essential for improving therapy outcomes. Based on these challenges, deeper investigation into tumor–immune communication mechanisms became necessary.
Researchers from Tianjin Medical University Cancer Institute & Hospital and collaborating institutions reported (DOI: 10.20892/j.issn.2095-3941.2025.0282) in Cancer Biology & Medicine that migration and invasion inhibitory protein (MIIP) suppresses colorectal cancer progression by regulating immune signaling within the tumor microenvironment. Through multi-omics analysis, cell experiments, and animal models, the team demonstrated that MIIP blocks M2 macrophage polarization via the STING–NFκB2–IL10 signaling axis. Their findings reveal how tumor cells and immune cells form a feedback loop that drives metastasis and identify a potential therapeutic target for patients who respond poorly to existing immunotherapies.
The researchers combined bioinformatics analyses, cellular experiments, co-culture systems, and mouse models to uncover MIIP's immunological role. Analysis of patient datasets showed that low MIIP expression correlated with activation of STING signaling, increased infiltration of M2 macrophages, and poorer clinical outcomes. Laboratory experiments confirmed that reducing MIIP levels increased cytoplasmic DNA stress signals, triggering STING activation and downstream NFκB2 signaling.This signaling cascade enhanced production of IL-10, an immunosuppressive cytokine known to drive macrophages toward the tumor-promoting M2 phenotype. In co-culture experiments, macrophages exposed to MIIP-deficient cancer cells displayed elevated M2 markers and secreted higher IL-10 levels. These macrophages, in turn, significantly increased cancer cell migration and invasion—demonstrating a self-reinforcing immune feedback loop.
Animal studies further validated the mechanism: tumors expressing higher MIIP levels showed reduced growth, fewer liver metastases, and diminished M2 macrophage infiltration. Importantly, blocking STING signaling reversed tumor-promoting effects caused by MIIP loss, highlighting the pathway's therapeutic relevance. Clinical tissue analyses confirmed negative correlations between MIIP expression and STING, IL-10, and macrophage infiltration, linking the molecular mechanism directly to patient prognosis.
According to the study authors, the findings redefine MIIP as more than a tumor suppressor acting inside cancer cells. Instead, MIIP serves as a regulator of immune communication within tumors. By controlling macrophage polarization, MIIP determines whether the tumor microenvironment becomes hostile or supportive to cancer growth. The researchers emphasize that targeting immune signaling pathways rather than tumor cells alone may represent a promising direction for future therapies, particularly for patients whose tumors do not respond to current immune checkpoint treatments.
The discovery opens new possibilities for precision immunotherapy in colorectal cancer. Measuring MIIP expression could help identify patients likely to benefit from therapies targeting the STING pathway or macrophage-mediated immune suppression. Pharmacological inhibition of STING signaling showed therapeutic potential in experimental models, suggesting a strategy for transforming immune-resistant tumors into treatment-responsive ones. Beyond colorectal cancer, the study highlights a broader principle: tumor progression can be controlled by reshaping immune cell behavior rather than directly killing cancer cells. Future therapies may therefore combine immune microenvironment modulation with existing treatments to reduce metastasis and improve long-term survival outcomes.
###
References
DOI
10.20892/j.issn.2095-3941.2025.0282
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0282
Funding information
This work was supported by grants from the National Natural Science Foundation of China [Grant No. 81871990 (Yan Sun)], the Key Project of Tianjin Natural Science Foundation [Grant No. 24JCZDJC00320 (Yan Sun)], the Key Project in 14th Five-Year Plan Special for Cancer Prevention and Treatment Research from Tianjin Cancer Institute [Grant No. YZ-06 (Yan Sun)], the Construction Project of Cancer Precision Diagnosis and Drug Treatment Technology from TUCIH [Grant No. ZLJZZDYYWZL13 (Yan Sun)], Tianjin Key Medical Discipline (Pathology) Construction Project [Grant No. TJYXZDXK-3-016C (Yan Sun)], Jining City Key Research and Development Program Project [Grant No. 2023YXNS062 (Shuai Chen)] and Jining Medical University Affiliated Hospital Talent Doctoral Research Fund Project [Grant No. 2024-BS-006 (Shuai Chen)], and Tangshan Science and Technology Project [Grant No. 2025150220C (Chenglu Lu)].
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world.