Is hyaluronic acid carcinogenic?

High-molecular-weight hyaluronic acid (HMW-HA) is considered a protective form. It stabilises the extracellular matrix, limits inflammation, and slows cell proliferation. In vivo, high-molecular-weight hyaluronic acid has demonstrated its ability to inhibit infiltration of pro-inflammatory immune cells in lung injury models and to restrict tumour cell migration and regeneration. This beneficial action of HMW-HA relies on its interaction with the CD44 receptor. Binding to CD44 prevents Rac1 activation and cyclin D1-dependent signalling, blocking tumour proliferation. The polymer reduces COX-2 and MMP production, enzymes overactive in cancers. HMW-HA acts as a free-radical scavenger, protecting fibroblasts from pro-carcinogenic oxidative effects.

The case is different for low molecular weight hyaluronic acid (LMW-HA). This pro-inflammatory form activates Toll-like receptor 4 (TLR4) on cancer and immune cells. LMW-HA thus stimulates tumour cell proliferation, invasion and migration. Short hyaluronic acid fragments stimulate angiogenesis, the formation of new blood vessels required for tumour growth. LMW-HA disrupts tight junction integrity in the lymphatic endothelium and enables cancer cell spread. This process accelerates metastasis and contributes to anticancer treatment resistance.

The mechanisms described above apply to hyaluronic acid naturally found in human tissues. No clinical study has shown that topical hyaluronic acid produces these effects.

While some sources consider hyaluronic acid a potential carcinogen, others show it could become a preferred therapeutic vector to improve targeted delivery of anticancer drugs. Indeed, as mentioned above, in normal tissues, hyaluronic acid receptors such as CD44 or RHAMM are expressed at low levels and require prior activation to interact with hyaluronic acid. In tumour tissues, these receptors are overexpressed, and CD44 predominates. This facilitates internalisation of hyaluronic acid by cancer cells, without prior activation, enabling this compound to act as a carrier for active molecules within tumours.

Given the non-specific toxicity of conventional chemotherapy, hyaluronic acid could serve as a drug delivery system to enhance target specificity and reduce side effects.

• Hyaluronic acid and paclitaxel : Paclitaxel is used in the treatment of breast cancer, ovarian cancer and melanoma. This anticancer agent has low water solubility and non-specific toxicity. Several studies have shown that conjugation with hyaluronic acid enhances its efficacy and stability. Some researchers added a fluorescent marker to hyaluronic acid nanoparticles bound to paclitaxel, enabling tracking in vivo and confirming preferential accumulation in tumour tissue.

• Hyaluronic acid and doxorubicin : Doxorubicin is an established oncology agent. It is known for cumulative toxicity. To address this issue, researchers developed stable hyaluronic acid–doxorubicin conjugates that target metastases. They showed that this combination delayed tumour progression and extended survival in animal models while reducing toxicity.

• Hyaluronic acid and cisplatin : Cisplatin is another standard chemotherapy agent but its use is limited by renal and neurological toxicity. Some studies have shown that conjugation with hyaluronic acid improves distribution in lymph nodes and tumour tissues. Other research has tested this combination as a treatment for head and neck squamous cell carcinoma in mice. It resulted in superior antitumour activity and reduced weight loss in treated animals with no signs of systemic toxicity.

Research into hyaluronic acid paves the way for more targeted, better-tolerated therapeutic strategies in cancer treatment. Preclinical data suggest that conjugating this compound with certain drugs could enhance efficacy while limiting toxicity, but clinical trials are still needed to confirm this.