Home›Oncology› Bidirectional crosstalk between hepatic stellate cell-derived CAFs and T cells drives immune evasion in HCC
Bidirectional crosstalk between hepatic stellate cell-derived CAFs and T cells drives immune evasion in HCCCell Communication May Drive Immune Resistance in Liver Cancer
Frontiers in MedicinePublished September 9, 2026Study authors: Kechuan Pan, Chunlian MaDOI ↗Editorial oversight: Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development
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Key Takeaway
Note that bidirectional crosstalk between HSC-derived CAFs and T cells promotes immune evasion in hepatocellular carcinoma.
This systematic review explores the role of bidirectional crosstalk between hepatic stellate cell-derived cancer-associated fibroblasts (CAFs) and T cells in the context of hepatocellular carcinoma (HCC). The review synthesizes evidence regarding how these interactions contribute to the tumor microenvironment.
Key findings indicate that HSC-derived CAFs can restrict the infiltration and function of effector T cells while promoting the accumulation of immunosuppressive cells. These CAFs utilize signaling networks including TGF-beta/SMAD, IL-6/STAT3, CXCL12/CXCR4, and CCL2/CCR2, alongside extracellular matrix remodeling, vascular abnormalities, hypoxia, and metabolic reprogramming. Conversely, cytokines from T-cell subsets, such as IL-17A, TGF-beta, IL-10, IFN-gamma, and TNF-alpha, can shape CAF activation and inflammatory states.
Several limitations are noted, including CAF heterogeneity, limited targeting specificity, and insufficient causal evidence in humans. Additionally, there are potential safety concerns regarding the management of these pathways in the setting of underlying liver disease. The crosstalk axis may provide a framework for understanding immune exclusion and therapeutic resistance, potentially informing future strategies in CAF modulation, stromal remodeling, and combination immunotherapy.
How this fits prior evidence
This systematic review addresses a gap in understanding the mechanisms of immune evasion and therapeutic resistance in hepatocellular carcinoma. It complements existing evidence regarding drug resistance driven by post-translational modifications and the role of NRF2 signaling in promoting tumor cell survival and multidrug resistance in advanced hepatocellular carcinoma. While the current review focuses on the stromal and T-cell crosstalk, previous findings established the roles of PTMs and NRF2 in driving resistance.
Researchers reviewed how different cells in the liver communicate with each other to influence the growth of hepatocellular carcinoma, a type of liver cancer. The study focused on the interaction between cancer-associated fibroblasts (CAFs) and T cells, which are the primary cells responsible for fighting infections and tumors.
The review found that these CAFs can block T cells from entering the tumor area and weaken their ability to fight the cancer. Instead, these cells promote the growth of other cells that suppress the immune system. This process can lead to immune evasion and make it harder for treatments to work. The study also identified specific signaling pathways and environmental factors, such as oxygen levels and tissue changes, that contribute to this environment.
It is important to note that this research is a systematic review of existing data and does not provide enough evidence to prove cause and effect in humans. There are also concerns regarding the safety of targeting these specific cells in patients with existing liver disease. While these findings offer a new way to understand why some treatments fail, they are not yet ready to change standard medical practices.
What this means for you:
Specific cell interactions in the liver may help cancer hide from the immune system and resist treatment.
Common questions
How do these cells help the cancer grow?
The study found that certain cells called CAFs can block the movement of T cells into the tumor. These CAFs also promote the growth of cells that turn off the immune response. This creates an environment where the cancer can hide from the body's natural defenses and become more resistant to treatment.
What are the risks of targeting these cells?
Because this was a review of existing data, specific safety results were not reported. However, the researchers noted that there are potential safety concerns when trying to target these specific cells in patients who already have underlying liver disease.
Is this a new treatment for liver cancer?
No, this is not a new treatment. The study is a review of how cells communicate. While it provides a framework for future research into combination therapies and better ways to identify patients, there is currently insufficient evidence to confirm how these findings will change human clinical care.
Hepatocellular carcinoma (HCC) commonly develops in the context of chronic liver injury and fibrosis, and its immune evasion and therapeutic resistance are shaped not only by tumor-intrinsic factors but also by persistent interactions between the tumor stroma and immune cells. Hepatic stellate cells (HSCs) represent an important source of cancer-associated fibroblasts (CAFs) in HCC. HSC-derived CAFs can restrict the infiltration and function of effector T cells and promote the accumulation of immunosuppressive cells through CAF-associated and multicellular signaling networks, including TGF-β/SMAD, IL-6/STAT3, CXCL12/CXCR4, and CCL2/CCR2, as well as through extracellular matrix remodeling, vascular abnormalities, hypoxia, and metabolic reprogramming. Importantly, mediators such as IL-6 and CCL2 are not specific to HSC-derived CAFs and can also be produced by immune cells, hepatocytes, and other cellular populations within the HCC microenvironment. Conversely, cytokines released by distinct T-cell subsets, including IL-17A, TGF-β, IL-10, IFN-γ, and TNF-α, can in turn shape CAF activation, inflammatory states, and matrix-remodeling programs, thereby establishing a dynamic immune–stromal feedback loop. Focusing on the heterogeneity of CAFs and T cells, this review systematically summarizes the major mechanisms underlying bidirectional crosstalk between HSC-derived CAFs and T cells and their stage-specific roles in chronic liver injury, HCC initiation, progression, and therapeutic resistance. We further discuss potential therapeutic strategies involving CAF modulation, stromal remodeling, combination immunotherapy, and patient stratification. Current evidence suggests that this crosstalk axis may provide an important framework for understanding immune exclusion and therapeutic resistance in HCC. However, its clinical translation remains constrained by CAF heterogeneity, limited targeting specificity, insufficient causal evidence in humans, and safety concerns in the setting of underlying liver disease.
