Enhance Immunotherapy

Promising Substances to Enhance Nivolumab/Immunotherapy

Compound	Category	Primary Mechanism with Anti-PD-1	Key Evidence / Rationale
Honokiol	Phytochemical	Dual-action: Degrades tumor PD-L1 + enhances T-cell infiltration. Attacks the PD-1/PD-L1 axis from the tumor side.	Direct mechanistic study: Mediates PD-L1 degradation, activates T-cells, and suppresses lung cancer growth in vivo (PMID: 38626551).
Phenylbutyrate	Repurposed Drug	HDAC inhibitor & Immunogenicity booster. Upregulates tumor antigen presentation and enhances CD8+ T-cell function.	Epigenetic modulation (HDAC inhibition), Enhanced antigen presentation, Ammonia metabolism modulation (Nature study), Direct T-cell functional enhancement
EGCG	Phytochemical	Targets Cancer Stem Cells (CSCs); direct pro-apoptotic effects. Addresses the root of relapse and resistance.	Direct preclinical study: Synergy with Nivolumab shown, specifically inducing CSC apoptosis.
Shikonin	Phytochemical	Induces Immunogenic Cell Death (ICD). Kills cancer cells in a way that alerts the immune system, converting "cold" tumors to "hot."	Direct mechanistic study: "Shikonin enhances the efficacy of PD-1 blockade in colorectal cancer by inducing immunogenic cell death."
Losartan	Repurposed Drug	Stromal normalization. Reduces tumor fibrosis & pressure, improving T-cell/drug delivery. A physical enabler.	Reverses immunosuppression by reshaping the microbiome and metabolome in colorectal cancer (PMID: 36724255).
Mistletoe	Herbal Extract	Broad immune activation. Stimulates NK/T-cells & cytokines; creates a "hotter," more inflamed TME.	Real-world data study shows prolonged overall survival when added to PD-1/PD-L1 blockade in NSCLC.
Fucoidan	Marine Compound	Immune enhancement & direct cytostatic effect. Boosts human immune cell activity in presence of Nivolumab.	Direct in-vitro study with Nivolumab on prostate cancer cells.
Evodiamine	Phytochemical	Elevates CD8+ T-cells; downregulates PD-L1. Attacks the pathway from multiple angles.	Study in non-small cell lung cancer showing immune and PD-L1 effects.
Thymoquinone	Phytochemical	Synergistic anti-tumor activity; modulates key signaling pathways.	Experimental models of renal cancer; case series in neuroendocrine carcinoma.
Metformin	Repurposed Drug	Metabolic modulator. Impacts cancer metabolism to improve T-cell function.	Phase II trial in colorectal cancer with Nivolumab.
Niclosamide	Repurposed Drug	Multi-pathway inhibitor. Targets STAT3, etc., to overcome resistance.	Preclinical study in non-small cell lung cancer.

References

1. Honokiol: Liu, B., et al. (2024). Honokiol suppresses non-small cell lung cancer growth by targeting PD-L1 for degradation and activating antitumor immunity. Phytomedicine. https://pubmed.ncbi.nlm.nih.gov/38626551/
2. Phenylbutyrate: HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases. Geetha Shanmugam, Sudeshna Rakshit, Koustav Sarkar. https://www.sciencedirect.com/science/article/pii/S193652332100303X
   Clinical Trial establishing safety | NaPB + VD resolves pathological inflammation
3. Ammonia death: a novel potential strategy to augment immunotherapy in cancer Zhi Li, Junyi Lin & Peihao Yin. https://www.nature.com/articles/s41417-024-00851-y
   Note: This study introduces the concept of targeting ammonia metabolism ("ammonia death") as a novel strategy to augment immunotherapy by enhancing T-cell function and tumor immunogenicity.
4. EGCG (Epigallocatechin-3-gallate): Al-Dosoki, M., et al. Flow cytometric assessment of nivolumab and/or epigallocatechin-3-gallate on cancer stem cells of DMBA induced hamster buccal pouch carcinoma. Medical Science. https://www.discoveryjournals.org/medicalscience/current_issue/v25/n118/A15.htm
5. Shikonin: Wang, F., et al. (2023). Shikonin enhances the efficacy of PD-1 blockade in colorectal cancer by inducing immunogenic cell death. Biochemical Pharmacology. https://www.researchgate.net/publication/370917834_Shikonin_enhances_the_efficacy_of_PD-1_blockade_in_colorectal_cancer_by_inducing_immunogenic_cell_death
6. Losartan: Liu, M., et al. (2023). Losartan reverses immunosuppression by reshaping the microbiome and metabolome in colorectal cancer. International Immunopharmacology. https://pubmed.ncbi.nlm.nih.gov/36724255/
7. Mistletoe (Viscum album L.): Freuding, M., et al. (2024). Patients with Advanced or Metastasised Non-Small-Cell Lung Cancer with Viscum album L. Therapy in Addition to PD-1/PD-L1 Blockade: A Real-World Data Study. Cancers, 16(8), 1609. https://www.mdpi.com/2072-6694/16/8/1609
8. Fucoidan: Fucoidan Independently Enhances Activity in Human Immune Cells and Has a Cytostatic Effect on Prostate Cancer Cells in the Presence of Nivolumab. Marine Drugs (2024). https://pubmed.ncbi.nlm.nih.gov/40186245/
9. Evodiamine: Liu, A., et al. (2020). Evodiamine suppresses non-small cell lung cancer by elevating CD8+ T cells and downregulating the MUC1-C/PD-L1 axis. Journal of Ethnopharmacology. https://www.researchgate.net/publication/347060304_Evodiamine_suppresses_non-small_cell_lung_cancer_by_elevating_CD8_T_cells_and_downregulating_the_MUC1-CPD-L1_axis
10. Thymoquinone: Potential therapeutic synergy of thymoquinone and nivolumab in experimental models of renal cancer. Journal of Natural Products (2023). https://www.researchgate.net/publication/362589900_EFFECT_OF_THYMOQUINONE_IN_COMBINATION_WITH_NIVOLUMAB_ON_EXPERIMENTAL_RENAL_CELL_CANCER_MODELS
11. Metformin: A Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer. Annals of Oncology (2022). https://www.researchgate.net/publication/374831881_Phase_II_trial_of_nivolumab_and_metformin_in_patients_with_treatment-refractory_microsatellite_stable_metastatic_colorectal_cancer
12. Niclosamide: Li, Y., et al. (2020). Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. Journal for ImmunoTherapy of Cancer. https://www.researchgate.net/publication/335765754_Niclosamide_an_antihelmintic_drug_enhances_efficacy_of_PD-1PD-L1_immune_checkpoint_blockade_in_non-small_cell_lung_cancer

Important Disclaimer: This information is for research and educational purposes only. The evidence presented is primarily from preclinical studies or early-phase clinical trials. None of these compounds are proven substitutes for standard cancer care. Combining any supplement or repurposed drug with immunotherapy like Nivolumab can be dangerous and may lead to reduced efficacy or severe side effects. It is absolutely essential that patients consult with their oncologist before considering any complementary approach. Last updated: October 2025.