Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Despite the success of immune checkpoint blockade therapies in various solid tumors, immunotherapy for CRC remains a challenge. Hence, there is a critical need to understand the complex tumor microenvironment (TME) of CRC and identify potential targets to develop new immunotherapies.

This research, published in the Genes & Diseases journal by a team from Xi’an Medical University, The First Hospital of China Medical University, and Air Force Medical University integrates single-cell and spatial transcriptomics with bulk sequencing to investigate the roles and mechanisms of SPP1⁺ macrophages in CRC.

The researchers identified four macrophage subsets from CRC tissue, including FCN1⁺ macrophages, C1QC⁺ macrophages, SPP1⁺ macrophages, and MKI67⁺ macrophages. They found that the number and proportion of SPP1⁺ macrophages consistently increased during CRC occurrence, progression, and metastasis. This finding suggests that SPP1⁺ macrophages play an important role in driving CRC development and metastasis.

Interestingly, this study noted an increase in the proportion of M1 macrophages and a decrease in M2 macrophages in CRC, contradicting the M1/M2 polarization theory. Functional analyses suggests that SPP1⁺ macrophages may promote CRC through epithelial-mesenchymal transition (EMT), hypoxia, glycolysis, and immunosuppressive pathways. These macrophages interact with other cells through the SPP1-CD44, SPP1- PTGER4, and SPP1 a4b1 complex axes, highlighting potential therapeutic intervention points.

In addition, the research findings suggest that preoperative chemotherapy can significantly reduce SPP1 expression in CRC macrophages, particularly in treatment responders, indicating a potential role in immunotherapy. Inhibition of the CSF1-CSF1R axis, a major research direction of macrophage-targeted immunotherapy, led to the depletion of the protective C1QC⁺ macrophage subset while sparing malignant SPP1⁺ macrophages. This drawback contributes to the poor efficacy of anti-CSF1R therapies in clinical studies.

In summary, this study provides a comprehensive analysis of SPP1⁺ macrophages in CRC, including their origin, distribution, clinical value, functional pathways, and implications for treatment. Based on the results, the researchers propose the SPP1⁺ macrophage model theory, which explains the changes in macrophages during CRC liver metastasis (CRLM) and guides clinical diagnosis and treatment. These findings open new avenues for CRC treatment and emphasize the need for more precise macrophage-targeted immunotherapy strategies.

Reference

Title of Original Paper: SPP1+ macrophages in colorectal cancer: Markers of malignancy and promising therapeutic targets

DOI: https://doi.org/10.1016/j.gendis.2024.101340

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

Funding Information:

National Natural Science Foundation of China (No. 82072655)
Scientific and technological innovation team of Shaanxi Innovation Capability Support Plan (China) (No. 2023-CX-TD-67)
Key R&D Plan of Shaanxi Province, China (No. 2022SF-603)

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