Migration and invasion inhibitory protein inhibits M2 macrophage polarization to suppress colorectal cancer progression through the STING–NFκB2–IL10 axis

Q: What is the main objective of this study?

To determine how MIIP modulates M2 macrophages in the tumor microenvironment and to assess the therapeutic potential of targeting the MIIP–STING pathway in colorectal cancer.

Q: How were MIIP and STING functions studied?

MIIP expression was analyzed using public datasets and clinical CRC samples, while CRC cells were genetically modified with lentiviral vectors to overexpress or silence MIIP and STING. Crosstalk was evaluated using co-culture and multiple molecular and functional assays, plus an orthotopic mouse CRC model.

Q: What does the STING–NFκB2–IL10 axis show in the results?

Low MIIP expression is linked to STING pathway activation and increased M2 infiltration. MIIP suppresses IL10 production via the STING–TRAF3–NFκB2 axis in CRC cells, reducing M2 polarization; M2 macrophages then enhance CRC migration and invasion in an IL10-dependent manner.

Sep 22, 2026

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This study determines how migration and invasion inhibitory protein (MIIP) regulates M2 macrophage behavior in the colorectal cancer tumor microenvironment and evaluates targeting MIIP–STING signaling for colorectal cancer therapy. MIIP associations with the STING pathway and M2 infiltration were assessed using public datasets and clinical samples; MIIP or STING was modulated in CRC cells, followed by co-culture, molecular, and functional assays. Orthotopic mouse models tested MIIP effects on polarization and metastasis. Results show low MIIP supports STING activation, increased M2 infiltration, and worse clinical outcomes, mediated by the STING–NFκB2–IL10 axis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Abstract

Objectives and Methods

Results

Conclusions

Introduction

Epidemiology and immune checkpoint inhibitor context

Background

Role of MIIP and tumor microenvironment shaping

Study Parts

Transcriptome analysis

Pathway identification

Animal model and clinical sample verification

Cancer Biol Med 2026. doi: 10.20892/j.issn.2095-3941.2025.0282 ORIGINAL ARTICLE Migration and invasion inhibitory protein inhibits M2 macrophage polarization to suppress colorectal cancer progression through the STING–NFκB2–IL10 axis Shuai Chen 1,2*, Chenglu Lu 1,3*, Jiaxin Li 1*, Xilin Shen 1, Yan Sun 1 1 Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin 300060, China; 2 Department of Pathology, Affiliated Hospital of Jining Medical University, Jining 272100, China; 3 Department of Pathology, Hebei Key Laboratory of Molecular Oncology, Tangshan People’s Hospital, Tangshan 063000, China | ABSTRACT | Objectives: This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein (MIIP) modulation inM2 macrophages within the tumor microenvironment and the potential of targeting the MIIP– stimulator of interferon genes (STING) pathway in colorectal cancer (CRC) therapy.
Methods: MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples. CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING. The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems. Techniques, including immunofluorescence staining, RT‒qPCR, western blot, ELISA, flow cytometry, and Transwell migration and invasion assays, were used to evaluate the crosstalk between CRC cells and macrophages. An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING–NFκB2–IL10 axis. The therapeutic significance of a STING antagonist was also assessed in vivo.
Results: Analyses of The Cancer Genome Atlas (TCGA) cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation, increased M2 macrophage infiltration, and poor clinical outcomes. The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING–TRAF3–NFκB2 axis in CRC cells, suppressing M2 macrophage polarization in co-culture systems. Conversely, M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner. In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING–NFκB2–IL10 axis. Furthermore, inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.
Conclusions: This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment, providing new insights into the role in suppressing CRC progression and immune–tumor crosstalk. These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors. | | --- | --- | | KEYWORDS | MIIP; M2 macrophage; STING; IL10; colorectal cancer | Introduction Colorectal cancer (CRC) ranks as the third most common malignancy and the second leading cause of cancer-related *These authors contributed equally to this work. Correspondence to: Yan Sun E-mail: [sunyan@tjmuch.com](sunyan@tjmuch.com) ORCID ID: [https://orcid.org/0000-0001-8916-9598](https://orcid.org/0000-0001-8916-9598) Received May 25, 2025; accepted September 24, 2025; published online January 14, 2026. Available [at www.cancerbiomed.org](at www.cancerbiomed.org) ©2026 The Authors. Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4 .0) deaths globally according to GLOBOCAN 20221. The 5-year survival rate for patients with advanced CRC in China is <20%, in large part due to disease recurrence and metastasis, despite comprehensive treatment strategi

FAQs

What is the main objective of this study?

To determine how MIIP modulates M2 macrophages in the tumor microenvironment and to assess the therapeutic potential of targeting the MIIP–STING pathway in colorectal cancer.

How were MIIP and STING functions studied?

MIIP expression was analyzed using public datasets and clinical CRC samples, while CRC cells were genetically modified with lentiviral vectors to overexpress or silence MIIP and STING. Crosstalk was evaluated using co-culture and multiple molecular and functional assays, plus an orthotopic mouse CRC model.

What does the STING–NFκB2–IL10 axis show in the results?

Low MIIP expression is linked to STING pathway activation and increased M2 infiltration. MIIP suppresses IL10 production via the STING–TRAF3–NFκB2 axis in CRC cells, reducing M2 polarization; M2 macrophages then enhance CRC migration and invasion in an IL10-dependent manner.

Sep 22, 2026

Upload by Theodore