Cancer Communications | Targeting SPHK1 Remodels Tumor Microenvironment and Enhances Anti-PD-1 Immunotherapy Efficacy in Colorectal Cancer Liver Metastasis

This study reveals that high SPHK1 expression in tumor-associated macrophages (TAMs) is significantly correlated with poor prognosis in colorectal cancer liver metastasis (CRLM) patients. Targeting SPHK1 effectively activates CD8+ T cells and remodels the immunosuppressive microenvironment, offering novel therapeutic strategies for CRLM patients.

 

Literature Overview
This article titled 'Targeting SPHK1 in macrophages remodels the tumor microenvironment and enhances anti-PD-1 immunotherapy efficacy in colorectal cancer liver metastasis' published in Cancer Communications summarizes SPHK1 expression in TAMs and its mechanistic role in CRLM immune therapy resistance. The research further analyzes how SPHK1 promotes TAM infiltration and induces CD8+ T cell exhaustion through regulating NLRP3 inflammasome and IL-1β release, leading to immunotherapy failure.

Background Knowledge
Colorectal cancer liver metastasis (CRLM) represents a common lethal complication in CRC patients, characterized by an immunosuppressive microenvironment that limits the efficacy of immune checkpoint inhibitors (ICIs). As primary immunosuppressive cells in CRLM, TAMs' heterogeneity and functional complexity make them a research priority for targeted therapies. While SPHK1 serves as a key enzyme regulating sphingolipid metabolism, its expression and functional role in TAMs remain unclear. This study employs multi-omics approaches and animal models to demonstrate SPHK1's pro-metastatic function in TAMs and proposes that targeting SPHK1 can reverse immunosuppressive microenvironment to enhance anti-PD-1 therapeutic effects.

 

 

Research Methods and Experiments
The research team evaluated SPHK1 expression in TAMs and its impact on TME using immunofluorescence, flow cytometry, Transwell migration assays, RNA sequencing, and mouse models. They observed effects of SPHK1 knockout or inhibition on TAM phenotypes, NLRP3 inflammasome activation, IL-1β release, and CD8+ T cell function. Additionally, the combination of anti-PD-1 therapy with SPHK1 inhibitors was assessed for antimetastatic effects and survival extension in mouse models.

Key Conclusions and Perspectives

• SPHK1 is highly expressed in TAMs from CRLM patients and shows significant correlation with poor prognosis.
• SPHK1 generates S1P to activate NLRP3 inflammasome in TAMs, promoting IL-1β secretion that induces TAM infiltration and CD8+ T cell exhaustion.
• SPHK1 knockout or inhibition significantly reduces TAM infiltration, enhances CD8+ T cell functionality, and delays CRLM progression.
• Combining SPHK1 inhibitors with anti-PD-1 therapy or radiotherapy substantially improves survival rates and suppresses liver metastasis in mouse models.

Research Significance and Prospects
This research identifies SPHK1 as a critical mediator in CRLM immune escape mechanisms and proposes targeting SPHK1 as a potential strategy to sensitize anti-PD-1 therapy. Future studies should evaluate SPHK1-targeted drugs' clinical translational potential in CRLM patients and explore their applicability in other immunosuppressive tumors.

 

 

Conclusion
This study systematically elucidates SPHK1's critical role in CRLM immune microenvironment. The findings demonstrate that SPHK1-overexpressing TAMs induce TAM infiltration and CD8+ T cell exhaustion through NLRP3-IL-1β pathway activation, thereby attenuating anti-PD-1 efficacy. Animal experiments confirm that SPHK1 targeting effectively remodels TME and enhances immunotherapy response. This work provides potential therapeutic targets for CRLM patients while establishing a foundation for future exploration of SPHK1's role in other cancer immunotherapies.

 

Yizhi Zhan, Jinsong Xu, Zhanqiao Zhang, Zhiyong Shen, and Yuan Fang. Targeting SPHK1 in macrophages remodels the tumor microenvironment and enhances anti‐PD‐1 immunotherapy efficacy in colorectal cancer liver metastasis. Cancer Communications.