Background: Colorectal cancer (CRC) is a leading cause of cancer-related death and is associated with high recurrence rates. Solute carrier family 7 member 5 (SLC7A5), a core transporter that facilitates the transmembrane movement of tryptophan, plays a role in various cancers. However, whether and how SLC7A5 promotes colorectal liver metastasis (CRLM) through tryptophan metabolism reprogramming and immune remodelling remain unexplored.
Methods: We integrated public datasets and clinical specimens to analyse SLC7A5 expression and prognosis, and validated its role in proliferation and metastasis using in vitro assays and in vivo models. Targeted metabolomics and isotope tracing identified kynurenine (Kyn) and xanthurenic acid (XANA) as downstream metabolites of SLC7A5. Single-cell RNA sequencing (scRNA-seq) and conditioned medium experiments were used to assess the impact of SLC7A5 on the tumour immune microenvironment (TIME).
Results: SLC7A5 expression increases sequentially in normal tissue, primary tumours and liver metastases, and higher SLC7A5 levels are associated with worse prognosis. SLC7A5 facilitates CRC cell growth, metastasis and epithelial‒mesenchymal transition (EMT) by promoting the production of Kyn and XANA and subsequent activation of the aryl hydrocarbon receptor (AhR). scRNA-seq analysis and conditioned medium experiments demonstrated that SLC7A5 knockdown reprograms the TIME by driving macrophages towards an antigen-presenting phenotype, alleviating CD8+ T-cell exhaustion, polarising CD4+ T cells towards Th1/Th17 subsets and triggering antigen-driven immunoglobulin G (IgG)-secreting B-cell clonal expansion, effects that were reversed by exogenous Kyn/XANA supplementation. Moreover, combination therapy with the SLC7A5 inhibitor JPH203 and anti-programmed cell death protein 1 (PD-1) antibody produced synergistic tumour growth inhibition and heightened antitumour immune responses.
Conclusions: Collectively, our findings reveal that SLC7A5 drives CRLM through tryptophan/Kyn/XANA–AhR signalling and concomitant remodelling of the TIME, positioning SLC7A5 as a promising target for combination therapy with anti-PD-1 in CRLM.
| [1] |
Koimtzis G, Geropoulos G, Stefanopoulos L, et al. The role of carbon nanoparticles as lymph node tracers in colorectal cancer: a systematic review and meta-analysis. Int J Mol Sci. 2023; 24(20):15293.
|
| [2] |
Liu S, Zhang Z, Wang Z, et al. SPP1 drives colorectal cancer liver metastasis and immunotherapy resistance by stimulating CXCL12 production in cancer-associated fibroblasts. Cancer Res. 2026; 86(1): 58-79.
|
| [3] |
Zhou M, Guan B, Liu Y, et al. Fibrinogen-like 2 in tumor-associated macrophage-derived extracellular vesicles shapes an immunosuppressive microenvironment in colorectal liver metastases by promoting tumor stemness and neutrophil extracellular traps formation. Cancer Lett. 2025; 618:217642.
|
| [4] |
Väyrynen V, Wirta EV, Seppälä T, et al. Incidence and management of patients with colorectal cancer and synchronous and metachronous colorectal metastases: a population-based study. BJS Open. 2020; 4(4): 685-692.
|
| [5] |
Opitz CA, Litzenburger UM, Sahm F, et al. An endogenous tumor-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011; 478(7368): 197-203.
|
| [6] |
Michaudel C, Danne C, Agus A, et al. Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases. Gut. 2023; 72(7): 1296-1307.
|
| [7] |
Duan S, Li X, Song C, et al. Isoliquiritigenin inhibits triple-negative breast cancer progression via targeting the IRF5/SLC7A5/IDO1-mediated tryptophan metabolism pathway. Oncol Res. 2025; 33(11): 3543-3556.
|
| [8] |
Lin YJ, Wu YC, Liu YJ, et al. Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance. Oncogenesis. 2025; 14(1): 26.
|
| [9] |
Huang R, Wang H, Hong J, et al. Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer. Front Immunol. 2023; 14:1251643.
|
| [10] |
Najumudeen AK, Ceteci F, Fey SK, et al. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nat Genet. 2021; 53(1): 16-26.
|
| [11] |
Fedoroff MY, Zhao L, Wang S, et al. Amino acid transporter LAT1 (SLC7A5) promotes metabolic rewiring in TNBC progression through the L-Trp/QPRT/NAD(+) pathway. J Exp Clin Cancer Res. 2025; 44(1): 190.
|
| [12] |
Venkateswaran N, Conacci-Sorrell M. Kynurenine: an oncometabolite in colon cancer. Cell Stress. 2020; 4(1): 24-26.
|
| [13] |
Pathria G, Verma S, Yin J, Scott DA, Ronai ZA. MAPK signaling regulates c-MYC for melanoma cell adaptation to asparagine restriction. EMBO Rep. 2021; 22(3):e51436.
|
| [14] |
Campesato LF, Budhu S, Tchaicha J, et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Nat Commun. 2020; 11(1): 4011.
|
| [15] |
Li S, Zhang Y, Luo M, et al. AR to GR switch modulates differential TDO2‒Kyn‒AhR signaling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer. Cell Discov. 2025; 11(1): 67.
|
| [16] |
Novikov O, Wang Z, Stanford EA, et al. An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER‒/PR‒/Her2‒ human breast cancer cells. Mol Pharmacol. 2016; 90(5): 674-688.
|
| [17] |
Badawy AA. Tryptophan metabolism and disposition in cancer biology and immunotherapy. Biosci Rep. 2022; 42(11):BSR20221682.
|
| [18] |
Yu L, Xu L, Chen Y, et al. IDO1 inhibition promotes activation of tumor-intrinsic STAT3 pathway and induces adverse tumor-protective effects. J Immunol. 2024; 212(7): 1232-1243.
|
| [19] |
Yamaguchi K, Tsuchihashi K, Ueno S, et al. Efficacy of pembrolizumab in microsatellite-stable, tumor mutational burden-high metastatic colorectal cancer: genomic signatures and clinical outcomes. ESMO Open. 2025; 10(1):104108.
|
| [20] |
Okano N, Naruge D, Kawai K, et al. First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2020; 38(5): 1495-1506.
|
| [21] |
Otani R, Takigawa H, Yuge R, et al. The anti-tumor effect of the newly developed LAT1 inhibitor JPH203 in colorectal carcinoma, according to a comprehensive analysis. Cancers (Basel). 2023; 15(5): 1383.
|
| [22] |
Zhao Y, Pu C, Liu K, Liu Z. Targeting LAT1 with JPH203 to reduce TNBC proliferation and reshape suppressive immune microenvironment by blocking essential amino acid uptake. Amino Acids. 2025; 57(1): 27.
|
| [23] |
Rii J, Sakamoto S, Mizokami A, et al. L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity. Cancer Sci. 2024; 115(3): 937-953.
|
| [24] |
Lu C, Liang L, Wu Y, et al. Slc7a5 promotes T cell anti-tumor immunity through sustaining cytotoxic T lymphocyte effector function. Oncogene. 2025; 44(41): 3939-3954.
|
| [25] |
Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010; 185(6): 3190-3198.
|
| [26] |
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372(26): 2509-2520.
|
| [27] |
Shalapour S, Lin XJ, Bastian IN, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 2017; 551(7680): 340-345.
|
| [28] |
Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020; 577(7791): 561-565.
|
| [29] |
Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020; 577(7791): 549-555.
|
| [30] |
Petitprez F, de Reyniès A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020; 577(7791): 556-560.
|
| [31] |
Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019; 575(7783): 512-518.
|
| [32] |
Puig-Kröger A, Sierra-Filardi E, Domínguez-Soto A, et al. Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages. Cancer Res. 2009; 69(24): 9395-9403.
|
| [33] |
Ramos RN, Missolo-Koussou Y, Gerber-Ferder Y, et al. Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer. Cell. 2022; 185(7): 1189-1207.e25.
|
| [34] |
Sharma A, Seow JJW, Dutertre CA, et al. Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma. Cell. 2020; 183(2): 377-394.e21.
|
Rights & permissions
2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
PDF
(8850KB)
