CBD Shrunk HPV-Positive Head and Neck Tumors by Boosting Immune Response in Mice | Research

The takeaway

CBD inhibited HPV-positive head and neck cancer cell growth in lab dishes and significantly reduced tumor volume in mice with intact immune systems, but had no effect in immune-deficient mice, proving the anti-tumor effect requires a working immune system.

Oncology researchers, immunotherapy developers, and head and neck cancer specialists.

What the researchers found

CBD activated the MAPK pathway (ERK1/2, JNK/SAPK, MK2), promoting apoptosis in cancer cells. In immunocompetent mice, CBD significantly reduced tumor growth and enhanced infiltration of CD4+T cells, CD8+T cells, B cells, NK cells, and M1-like macrophages. No anti-tumor effect was seen in immune-deficient mice. CD4+ T cell depletion reversed CBD's benefit, confirming immune dependence.

Why it matters

This is the first preclinical demonstration that CBD's anti-tumor activity in HPV-positive head and neck cancer depends entirely on the immune system rather than direct cancer cell killing alone. This has implications for combining CBD with immunotherapy approaches.

The numbers in context

CBD activated ERK1/2, JNK/SAPK, and MK2 via MAPK pathway. Significant tumor growth inhibition in immunocompetent mice only. Enhanced infiltration of CD4+T, CD8+T, CD19+B cells, NK cells, and M1 macrophages. CD4 depletion reversed anti-tumor effect. Multiplex IHC showed co-localization of T cells with phospho-p38 MAPK.

How the study worked

In vitro: BrdU proliferation, apoptosis, migration, and western blot analyses on HPV-positive HNSCC cells. In vivo: syngeneic mouse models (immunocompetent), Rag1 knockout mice (no T/B cells), and athymic nude mice (no T cells). Immune depletion experiments targeted CD4+ and CD8+ T cells. Flow cytometry, IHC, and multiplex IHC measured immune infiltration.

What this study cannot tell us

Mouse models do not fully recapitulate human HPV-positive HNSCC. CBD doses and routes used in mice may not translate to achievable human concentrations. Syngeneic models use mouse cancer cells, not human tumors. No comparison with standard of care treatments. Association between marijuana use and HPV-positive HNSCC adds complexity to clinical translation.

How to read the evidence

Comprehensive preclinical study with in vitro and multiple in vivo models including elegant immune depletion experiments, but translation to human cancer requires clinical trials.

When this study was published

Published 2025.

The bigger picture

HPV-positive head and neck cancers are increasing globally. The finding that CBD's anti-cancer effect is immune-mediated opens the possibility of combining CBD with checkpoint inhibitors or other immunotherapies, potentially enhancing treatment responses in this growing patient population.

Questions still open

Whether CBD combined with immune checkpoint inhibitors would enhance anti-tumor responses in HPV-positive HNSCC
How the paradox of marijuana use being associated with HPV-positive HNSCC while CBD shows anti-tumor activity is resolved

Common questions

Could CBD treat head and neck cancer in humans?

This is a preclinical study in mice that shows a promising mechanism. Whether CBD concentrations achievable in humans would produce similar effects is unknown. The findings suggest CBD might be worth studying as a complement to immunotherapy, not as a standalone cancer treatment.

Why does CBD need the immune system to fight cancer?

CBD appears to activate immune cells (T cells, NK cells, macrophages) to attack the tumor rather than killing cancer cells directly on its own. When the researchers removed immune cells, CBD had no effect on tumors, proving the immune system does the actual tumor-fighting work.

Read the original research

CBD promotes antitumor activity by modulating tumor immune microenvironment in HPV associated head and neck squamous cell carcinoma.

Frontiers in immunology, 16, 1528520

View on PubMed ↗Publisher’s paper ↗

Citation

Sen, Prakriti; Sadat, Sayed; Ebisumoto, Koji; Al-Msari, Riyam; Miyauchi, Sayuri; Roy, Souvick; Mohammadzadeh, Pardis; Lips, Kristin; Nakagawa, Takuya; Saddawi-Konefka, Robert; Sharabi, Andrew B; Califano, Joseph A. (2025). CBD promotes antitumor activity by modulating tumor immune microenvironment in HPV associated head and neck squamous cell carcinoma.. Frontiers in immunology, 16, 1528520. https://doi.org/10.3389/fimmu.2025.1528520