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Comprehensive Integrative Strategies for Liver Metastasis: Mechanisms, Biological Features, and Emerging Clinical Treatment Models

Mechanisms, biological characteristics and new clinical treatment models

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Clinical Significance of Liver Metastasis

The liver is one of the most common organs for tumor metastasis. Due to its vascular anatomy (dual blood supply), malignant tumor cells can easily disseminate to the liver via the portal vein or hepatic artery. Epidemiological data show that up to 50% of colorectal cancer patients, 20–30% of breast cancer patients, and 30–40% of lung cancer patients will develop liver metastases during the course of their disease (Tsilimigras et al., 2021).

Liver metastases not only cause impaired liver function, jaundice, and ascites but also significantly shorten overall survival. Without treatment, the median survival of patients with liver metastases is only about 4–8 months; with aggressive treatment, the five-year survival rate can reach 25–50% in selected cases (UpToDate, 2025). This underscores liver metastasis as a key battleground in oncology.

Immunological Mechanisms of Liver Metastasis

Hepatic Immune Tolerance

As the “immune buffer” of the digestive system, the liver must tolerate the constant influx of antigens from the gut to avoid excessive inflammation. However, this immune tolerance also creates a favorable environment for tumor cells to evade immune surveillance (AACR Clinical Cancer Research, 2021).

Liver metastatic niches are often characterized by:

  • Regulatory T cell (Treg) accumulation → suppressing effector immune responses
  • Myeloid-derived suppressor cells (MDSCs) → releasing immunosuppressive cytokines
  • Dysfunctional dendritic cells → reduced antigen presentation

These factors explain why PD-1/PD-L1 inhibitors show lower response rates in patients with liver metastases (Hegde & Chen, 2020).

A new concept, the Liver Metastasis Cluster Immune-Frame (LMCIF), categorizes patients based on immune infiltration patterns. This index can predict immunotherapy response and prognosis (Zhang et al., 2023).

Clinical Treatment Strategies

  • For patients with limited and resectable liver metastases, hepatectomy remains the only potentially curative option. Five-year survival can reach 30–58%, significantly better than systemic therapy alone (UpToDate, 2025).

  • Radiofrequency ablation (RFA): Effective for lesions <3 cm.
  • Cryoablation: Destroys tumor cells while releasing antigens, potentially triggering immune responses (Interventional Oncology, 2025).
  • Selective internal radiation therapy (SIRT/TARE): Yttrium-90 microspheres injected into the hepatic artery concentrate radiation in tumor sites, suitable for unresectable, diffuse metastases (Salem et al., 2010).
  • Hepatic arterial infusion chemotherapy (HAI): Delivers high local drug concentration with reduced systemic toxicity, but requires systemic therapy to lower recurrence risk (Wikipedia, 2025).
  • Chemotherapy: FOLFOX and FOLFIRI are standard for colorectal liver metastases.
  • Targeted therapy: Bevacizumab inhibits angiogenesis.
  • Immunotherapy: PD-1/PD-L1 inhibitors show limited efficacy in liver metastasis, but combination with radiotherapy may enhance outcomes (Nabrinsky et al., 2022).

  • Stereotactic body radiotherapy (SBRT) allows precise treatment of small liver metastases and may induce the abscopal effect, where distant tumors regress after localized radiation (Demaria et al., 2004).

Application of Integrative Therapies in Liver Metastasis

Immunonutrition

Studies show that immunonutrition (arginine, omega-3, glutamine) improves immune function, reduces infection rates, and shortens hospital stays. In patients undergoing surgery or radiotherapy for liver metastases, it enhances recovery (Arends et al., 2021).

Anti-inflammatory Diet

●Mediterranean diet: Reduces systemic inflammation and improves metabolism (De Cicco et al., 2021). ●Polyphenols: Green tea catechins and curcumin show immunomodulatory and antitumor effects (Hsu et al., 2021). ●Adequate protein: Prevents cachexia and supports liver and immune function.

Exercise Therapy

Aerobic and resistance training enhance immune surveillance, reduce cancer-related fatigue, and improve muscle mass (Campbell et al., 2019).

Psychological and Supportive Care

Mindfulness meditation, music therapy, and acupuncture reduce anxiety and insomnia, improving quality of life for cancer patients (Greenlee et al., 2017).

Multidisciplinary Care Model

A multidisciplinary team (MDT) is the gold standard in managing liver metastases. The ideal MDT includes:

  • Surgeons (resection/ablation)
  • Oncologists (systemic therapy)
  • Radiation oncologists (SBRT planning)
  • Interventional radiologists (SIRT/HAI procedures)
  • Nutritionists (immunonutrition)
  • Psychologists and integrative medicine specialists (supportive therapies)

This model enables personalized, comprehensive treatment planning to maximize survival and maintain quality of life (Deng et al., 2021).

Future Directions

  1. Immunotherapy combined with radiotherapy/SIRT: Clinical trials are needed to improve immunogenicity in “cold” tumors.
  2. Biomarker development: LMCIF and ctDNA monitoring may become predictive tools for treatment response.
  3. Integrative medicine trials: Nutrition, exercise, and psychosocial interventions should be incorporated alongside standard treatments.

Conclusion

Liver metastasis remains one of the most challenging aspects of oncology. Traditionally dominated by surgery, interventional procedures, and systemic therapies, treatment is now evolving into a new paradigm: tumor control + immune modulation + quality-of-life enhancement.

Combining local therapies, immunotherapy, and integrative approaches not only extends survival but also improves overall well-being.

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References

  • Arends, J., et al. (2021). ESPEN guidelines on nutrition in cancer patients. Clinical Nutrition, 40(5), 2898–2913.
  • Campbell, J. P., et al. (2019). Exercise and the immune system. Trends in Immunology, 40(7), 629–641.
  • De Cicco, P., et al. (2021). Nutrition and breast cancer. Nutrients, 13(11), 3889.
  • Demaria, S., et al. (2004). Immune-mediated inhibition after local radiation. Clinical Cancer Research, 10(2), 531–539.
  • Deng, G., et al. (2021). Integrative oncology practice at academic cancer centers. CA: A Cancer Journal for Clinicians, 71(2), 120–138.
  • Greenlee, H., et al. (2017). Integrative therapies for breast cancer patients. Journal of Clinical Oncology, 35(18), 1962–1981.
  • Hegde, P. S., & Chen, D. S. (2020). Top challenges in cancer immunotherapy. Immunity, 52(1), 17–35.
  • Hsu, C. H., et al. (2021). Natural compounds and cancer therapy. Frontiers in Pharmacology, 12, 665999.
  • Interventional Oncology. (2025). Minimally invasive tumor-directed therapies. Wikipedia.
  • Nabrinsky, E., et al. (2022). Abscopal effect in immunotherapy era. Cureus, 14(9), e29620.
  • Salem, R., et al. (2010). Radioembolization outcomes. Gastroenterology, 138(1), 52–64.
  • Tsilimigras, D. I., et al. (2021). Liver metastases. Nature Reviews Disease Primers, 7(1), 27.
  • UpToDate. (2025). Potentially resectable colorectal cancer liver metastases.
  • Zhang, L., et al. (2023). Immune signatures of liver metastases. ScienceDirect.
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