Enhancing Tumor Immunity in CRC through ACSL4 Knockdown

Introduction to ACSL4 and its Role in Colorectal Cancer

Long-chain acyl-CoA synthetase 4 (ACSL4) has emerged as a pivotal player in the interplay between metabolism and cancer progression, particularly in colorectal cancer (CRC). Elevated ACSL4 expression has been documented in various malignancies, including CRC, and is associated with poor patient outcomes. Its role extends beyond mere involvement in lipid metabolism; ACSL4 is also intricately linked to ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. In CRC, ACSL4’s function in promoting tumor growth and immune evasion complicates the treatment landscape, necessitating a deeper understanding of its mechanisms (Liu et al., 2025).

Research indicates that ACSL4 inhibition can restore anti-tumor immune responses by enhancing the expression of major histocompatibility complex (MHC) class I molecules on tumor cells, thereby improving T-cell recognition and cytotoxicity. This study explores how ACSL4 knockdown can modulate the immune microenvironment in CRC, potentially leading to enhanced therapeutic efficacy through immune checkpoint blockade (ICB) approaches.

Impact of ACSL4 Expression on Patient Prognosis

High ACSL4 levels in CRC tissues correlate significantly with decreased overall survival rates among patients. Utilizing bioinformatics tools such as the Gene Expression Profiling Interactive Analysis (GEPIA) and GEO databases, it has been observed that ACSL4 expression is markedly higher in CRC compared to normal colorectal tissues. Furthermore, the PROGgeneV2 database analyses affirm that patients with elevated ACSL4 expression exhibit poorer prognostic outcomes (Liu et al., 2025).

In the context of the AOM/DSS-induced colon cancer model, researchers have shown that ACSL4 levels are upregulated in tumor tissues compared to adjacent non-cancerous tissues. This upregulation not only signifies the necessity for ACSL4 as a prognostic marker but also highlights its potential as a therapeutic target for CRC. The correlation between ACSL4 expression and tumor characteristics such as size and stage further emphasizes its relevance in cancer biology.

Mechanisms of ACSL4 in Modulating Anti-Tumor Immunity

ACSL4 influences the tumor immune microenvironment by modulating the RIG-I-MAVS-IFN pathway. This pathway plays a critical role in the immune response against tumors, particularly by enhancing MHC class I antigen presentation. When ACSL4 is knocked down, there is a notable increase in CD3⁺ and CD8⁺ T cell infiltration into tumors, indicating a more robust anti-tumor immune response. The study delineates that ACSL4 knockdown leads to the upregulation of chemokines such as CXCL10 and CXCL11, which are crucial for T cell recruitment (Liu et al., 2025).

Additionally, the upregulation of antigen presentation machinery, including genes such as TAP1, TAPBP, and H2k1, illustrates the potential of ACSL4 as a target for immunotherapy. The enhanced expression of these genes facilitates improved recognition of tumor cells by the immune system, thereby fostering a more effective immune-mediated attack on the tumor.

ACSL4 Knockdown Effects on Tumor Growth and Immune Infiltration

Experiments conducted using ACSL4 knockdown in murine CRC models demonstrated a significant reduction in tumor growth and weight in immunocompetent mice. This effect was markedly diminished in immunodeficient mice, underscoring the importance of an intact immune system in mediating the anti-tumor effects of ACSL4 inhibition. Flow cytometry and immunohistochemical analyses revealed an increase in the infiltration of CD3⁺ and CD8⁺ T cells in tumor sites following ACSL4 knockdown.

The immunogenicity of tumors is further enhanced by the upregulation of interferon-stimulated genes (ISGs) and the activation of the RIG-I-MAVS pathway, which promotes a favorable immune environment conducive to T cell activity. These findings suggest that targeting ACSL4 could convert “cold” tumors into “hot” tumors, thereby improving responses to immune checkpoint inhibitors (Liu et al., 2025).

Therapeutic Implications of Targeting ACSL4 in CRC Treatment

The implications of targeting ACSL4 in CRC therapy are profound. By enhancing anti-tumor immunity through ACSL4 knockdown, there is a potential to improve patient responses to existing immunotherapies such as PD-1/PD-L1 inhibitors. The study highlights that ACSL4’s modulation of the immune landscape can synergize with ICB therapies, leading to improved clinical outcomes.

In conclusion, the targeting of ACSL4 not only provides a strategy to enhance the efficacy of immunotherapy in CRC but also emphasizes the need for further investigation into the role of metabolic enzymes in cancer immunology. As research progresses, ACSL4 may emerge as a critical therapeutic target in the fight against colorectal cancer.

FAQs

What is ACSL4?

ACSL4 (long-chain acyl-CoA synthetase 4) is an enzyme involved in fatty acid metabolism and is implicated in the regulation of ferroptosis and tumor progression.

How does ACSL4 affect colorectal cancer?

ACSL4 is overexpressed in colorectal cancer tissues and is associated with poor prognosis. Its modulation can enhance anti-tumor immunity, potentially improving responses to immunotherapies.

What is the significance of the RIG-I-MAVS pathway?

The RIG-I-MAVS pathway is crucial for the immune response against tumors. It enhances MHC class I expression, facilitating T cell recognition and attack on cancer cells.

How can ACSL4 knockdown impact tumor growth?

ACSL4 knockdown has been shown to suppress tumor growth in immunocompetent models by increasing T cell infiltration and enhancing the immune response against the tumor.

What are the therapeutic implications of targeting ACSL4?

Targeting ACSL4 could improve the efficacy of immune checkpoint inhibitors in colorectal cancer, converting cold tumors into hot tumors that are more responsive to treatment.

References

1. Liu, Y., Jiang, X., Jing, D., Lin, Y., Gao, R., Zhao, Q., Da, H., Ren, Y., Cao, Q., Liu, N., Han, X., Du, J., & Gao, X. (2025). ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity. Neoplasia. https://doi.org/10.1016/j.neo.2025.101194

2. Edmondson, J. L., Reed, M. R., Fil, D., Heflin, B., McKinnon, A., Bauer, M. A., Morehead, L. C., Avaritt, N. L., Phillips, M., Taverna, S. D., Tackett, A. J., & Koss, B. (2025). EZH2 loss during metabolic stress drives restoration of MHC class I machinery in melanoma. Cell Reports. https://doi.org/10.1016/j.celrep.2025.115690

3. Chen, Y.-W., Ahn, I.-S., Wang, S. S.-M., Majid, S., Diamante, G., Cely, I., Zhang, G., Cabanayan, A., Komzyuk, S., Bonnett, J., Arneson, D., & Yang, X. (2025). Multitissue single-cell analysis reveals differential cellular and molecular sensitivity between fructose and high-fat high-sucrose diets. Cell Reports. https://doi.org/10.1016/j.celrep.2025.115690

4. Insights from precision-cut lung slices—investigating mechanisms and therapeutics for pulmonary hypertension. (2025). Respiratory Research. https://doi.org/10.1186/s12931-025-03290-x