Colorectal cancer (CRC) is one of the most common malignancies and is the second leading cause of cancer-related death worldwide. While immune checkpoint inhibitors (ICIs) are indicated as a first-line treatment for metastatic CRC (mCRC), the microsatellite stable (MSS) subgroup exhibits primary resistance to this form of immunotherapy. Investigating the potential mechanisms underlying this poor response to immunotherapy in the majority of CRCs is crucial for improving the prognosis of CRC patients.

The tumor microenvironment (TME) is a complex and heterogeneous cellular environment composed of various cell types. Several factors associated with the dysregulation of the TME may contribute to the resistance of CRC patients to ICI-based immunotherapy. The heightened metabolic activity within the TME can lead to the depletion of key nutrients and accumulation of waste products. To this end, Prof. FANG Weijia, Prof. CHEN Wenbin, and Dr. BAO Xuanwen from the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZU) conducted a study on immunometabolism molecular subtyping (IMS). This was based on a comprehensive analysis of the transcriptome, proteome, and single-cell transcriptome in public training cohorts and in-house validation cohorts. The corresponding study was published in the journal Cell Reports Medicine, entitled “An immunometabolism subtyping system identifies S100A9⁺ macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis”.

Figure 1: Three immunometabolism subtypes (C1, C2, C3) exhibit distinct metabolic and immunogenic characteristics. In the C3 subtype, a population of S100A9⁺ macrophages contributes to the immunosuppressive tumor microenvironment. The combination of PD-1 blockade and tasquinimod improves responses to immunotherapy. 

In this study, the researchers introduced an immunometabolism (IMS) system by integrating transcriptomic, proteomic, and metabolomic data. Three subtypes were identified to stratify CRC patients with different prognoses. The C3 subtype, characterized by high abundance of S100A9⁺ macrophages, was associated with a poor outcome. S100A9⁺ macrophages exhibited the capacity to influence T cells through cell-cell interaction in the C3 subtype of CRC. Targeting S100A9+ macrophages in combination with immune checkpoint blockade may present a promising approach to reverse immune escape and enhance the efficacy of immunotherapy in specific immunometabolism subtypes of CRC patients.

More information:The corresponding authors are Prof. FANG Weijia, Director of the Department of Medical Oncology III of FAHZU, Visiting scholar of Hong Kong University, and Member of the Standing Committee of Liver Cancer and biliary Cancer Expert Committee of the Chinese Society of Clinical Oncology, and Prof. CHEN Wenbin, Deputy Director of Zhejiang Colorectal Disease Diagnosis and Treatment Center, President of Anorectal Physician Branch of Zhejiang Medical Doctor's Association, and Chairman of Anorectal Surgery Branch of Zhejiang Medical Association. The first author is Dr. BAO Xuanwen, physician of the Department of Medical Oncology III of FAHZU.

Source: The First Affiliated Hospital, Zhejiang University School of Medicine