Is hyaluronic acid carcinogenic?

High-molecular-weight hyaluronic acid (HMW-HA) is considered a protective form. It stabilizes the extracellular matrix, limits inflammation, and slows cellular proliferation. In vivo, high-molecular-weight hyaluronic acid has inhibited infiltration of proinflammatory immune cells in lung injury models and restricted tumor cell migration and regeneration. This action relies on interaction with the CD44 receptor. When bound to CD44, HMW-HA prevents Rac1 activation and cyclin D1–dependent signaling, blocking tumor proliferation. This polymer reduces COX-2 and MMP production, proinflammatory enzymes often overactive in cancers. HMW-HA acts as a free radical scavenger, protecting fibroblasts from procarcinogenic oxidative effects.

Low-molecular-weight hyaluronic acid (LMW-HA) is different. This proinflammatory form activates Toll-like receptors (TLR), including TLR4, on cancer and immune cells. LMW-HA stimulates the proliferation, invasion, and migration of tumor cells. Short hyaluronic acid fragments stimulate angiogenesis, the formation of new blood vessels needed for tumor growth. LMW-HA contributes to loss of tight junction integrity in the lymphatic endothelium, enabling rapid cancer cell dissemination. This process accelerates metastasis and contributes to resistance to anticancer treatments.

The mechanisms described above apply to hyaluronic acid naturally present in human tissues. No clinical study has shown that hyaluronic acid applied to the skin has these effects.

Although some sources consider hyaluronic acid potentially carcinogenic, others reveal it could become a vector of choice to improve targeted delivery of anticancer drugs. Indeed, as noted 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 contrast, in tumor tissues, these receptors are overexpressed, especially CD44. This facilitates the internalization of hyaluronic acid by cancer cells, without prior activation, allowing this agent to serve as a vector to deliver active molecules into tumors.

Given the non-specific toxicity of conventional chemotherapy, using hyaluronic acid as a drug delivery system could improve specificity and limit side effects.

• Hyaluronic acid and paclitaxel : Paclitaxel is a molecule used to treat breast cancer, ovarian cancer, and melanoma. This anticancer agent has low water solubility and nonspecific toxicity. Studies have shown that conjugation to 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 tumor tissues.

• Hyaluronic acid and doxorubicin : Doxorubicin is another major oncology agent. It is known for cumulative toxicity. To overcome this limit, some researchers designed stable hyaluronic acid-doxorubicin conjugates capable of targeting metastases. They showed that this combination delayed tumor progression and extended animal survival while reducing toxicity.

• Hyaluronic acid and cisplatin : Cisplatin is another reference chemotherapy agent, but its use is limited by renal and neurological toxicity. Some studies have shown that conjugating it with hyaluronic acid improves distribution in lymph nodes and tumor tissues. Other studies have used this combination to treat head and neck squamous cell carcinoma in mice. The result: enhanced antitumor efficacy and reduced weight loss in treated animals, with no signs of systemic toxicity.

Research on hyaluronic acid is paving the way for more targeted and better-tolerated cancer treatment strategies. Preclinical data suggest that conjugating this compound with certain drugs could improve their efficacy while limiting toxicity, but clinical trials are needed to confirm this.