Regulatory T cells shape immune escape in liver metastases across cancer types
image: ATP, adenosine triphosphate; CCL, chemokine (C-C motif) ligand 2; CCR, C-C motif chemokine receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; FoxP3, forkhead box P3; eTreg, effector Treg; HSC, hepatic stellate cell; ICOS, inducible costimulatory; ICOSL, ICOS ligand; IL, interleukin; iTreg, induced Treg; LAG3, lymphocyte activating 3; LSEC, liver sinusoidal endothelial cells; MHC, major histocompatibility complex; NETs, neutrophil extracellular traps; neu, neutrophil; NK, natural killer; nTreg, natural Treg; PD-1, programmed cell death-protein 1; TCR, T cell receptor; Teff, effector T cell; TGF-β, transforming growth factor-beta; Treg, regulatory T cell.
Credit: By Grace Wu, Hai Huang, et al.
A unique immune landscape in liver metastases
Liver metastases (LMs) are associated with worse survival and markedly reduced responses to immune checkpoint inhibitors across multiple solid tumors. While immunotherapy has transformed outcomes in melanoma, lung cancer and renal cell carcinoma, response rates in patients with hepatic metastases are consistently below 25%. The liver's specialized immune environment, which is evolved to maintain tolerance to gut-derived antigens, creates a permissive niche for metastatic tumour growth. Within this setting, regulatory T cells (Tregs) emerge as key orchestrators of local and systemic immunosuppression.
Regulatory T cells: from immune homeostasis to tumour tolerance
Tregs are a specialized subset of CD4⁺ T cells defined by high expression of FOXP3 and CD25. Under physiological conditions, they are essential for preventing autoimmunity and controlling excessive inflammation. In cancer, however, Tregs are frequently co-opted by tumors to suppress antitumor immunity. The review highlights how hepatic Tregs inhibit cytotoxic CD8⁺ T cells through multiple mechanisms, including secretion of immunosuppressive cytokines (IL-10, TGF-β), metabolic competition for IL-2, and expression of immune checkpoints such as CTLA-4 and PD-1.
Importantly, Tregs in liver metastases are not a uniform population. Their phenotype and function vary depending on tumour origin, stage of disease and interactions with liver-resident cells such as Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells, all of which actively promote Treg differentiation and activation.
Divergent roles across primary tumour types
A central message of the review is that the impact of Tregs in liver metastases is highly context dependent. In colorectal cancer (CRC), for example, Tregs may play a protective, anti-inflammatory role in primary tumors arising from chronic gut inflammation. Yet once metastases develop in the liver, activated Tregs correlate with higher Treg-to-effector T-cell ratios, impaired CD8⁺ infiltration and poorer survival. Similar tumour-specific patterns are described in breast, pancreatic, gastric, lung and melanoma liver metastases, underscoring that Treg number alone is an insufficient prognostic marker. Instead, their functional state and spatial distribution within the tumour microenvironment are critical.
Tregs and immunotherapy resistance
The review provides compelling evidence that Tregs are central mediators of immunotherapy resistance in liver metastases. Preclinical models demonstrate that immune checkpoint blockade can paradoxically expand highly suppressive Treg subsets within the liver, blunting therapeutic efficacy. Clinical observations mirror these findings, with liver metastases often acting as "immune sinks" that induce systemic tolerance and reduce responses even at extrahepatic sites.
These insights help explain why checkpoint inhibitor monotherapy is frequently ineffective in patients with hepatic metastases. They also support emerging strategies that combine PD-1/PD-L1 blockade with agents that deplete or reprogram Tregs, such as CTLA-4 inhibitors, TIGIT blockade, CXCR4 antagonists or liver-directed therapies.
Implications for surgery and radiotherapy
Beyond systemic therapy, the authors highlight the underappreciated role of Tregs in surgery- and radiotherapy-associated immune modulation. Surgical stress and local radiotherapy can alter the hepatic immune microenvironment, potentially promoting metastatic seeding through Treg expansion. Understanding how Tregs respond to these interventions may inform perioperative or combinatorial strategies aimed at reducing postoperative recurrence in patients undergoing liver resection.
Looking ahead: precision immunotherapy for liver metastases
This comprehensive review reframes liver metastases not merely as tumour deposits, but as immunologically active sites shaped by complex Treg-driven interactions. The authors argue that effective treatment will require precision approaches that account for tumour origin, Treg heterogeneity and the unique tolerogenic features of the liver. As next-generation immunotherapies and combination regimens evolve, targeting Tregs within the hepatic metastatic niche may be key to overcoming one of the most persistent barriers in cancer treatment.
Conclusion
Regulatory T cells are key drivers of immune tolerance and therapy resistance in liver metastases, shaped by both tumour origin and the hepatic microenvironment. Their context-dependent roles highlight the need for combination strategies that target Tregs alongside immunotherapy to overcome resistance and improve clinical outcomes.
See the article:
Wu G, Yang T, Gholami S, et al. Regulatory T cells in liver metastases: emerging and divergent roles in tumour progression. eGastroenterology 2025;3:e100257. doi:10.1136/egastro-2025-100257
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