Researchers have created a new vaccine for the treatment of late-stage metastatic melanoma, an aggressive skin cancer that can resist conventional treatments because it exists in an ecosystem that suppresses the body’s immune response.

This immunosuppressive tumor microenvironment prevents therapies from effectively targeting and eliminating cancer cells. While other cancer interventions, such as targeted therapies and existing immunotherapeutics, have shown some efficacy with melanoma, this environment can cause immune-related adverse effects and rapid tumor relapse, the return of cancer after a period of remission or when it’s thought to be under control.

This problem is one that is vital to overcome, with melanoma being the most common fatal form of skin cancer. The American Cancer Society estimates that during 2025 and in the U.S. alone, around 104,960 new melanomas will be diagnosed, and an estimated 8,430 people will die as a result of melanoma. 

This has led to interest in the development of tumor-associated antigen-based cancer vaccines that use antigens expressed by tumor cells to stimulate an immune response. These vaccines aim to activate antigen-presenting cells to prime cancer-killing cytotoxic cells, or “killer T cells,” and helper T cells, which coordinate the body’s immune response. Tumor-associated antigen-based cancer vaccines offer an alternative treatment strategy for patients who do not respond well to immune checkpoint inhibitors or adoptive T-cell therapies that use a patient’s own T cells to fight cancer. These vaccines are also helpful for tumors that express known antigens, cells that trigger a systemic immune response suitable to control or eradicate tumor growth. 

However, tumor-associated antigen-based cancer vaccines are far from perfect, hence the development of this new vaccine, described in a new paper published in the journal Advanced Materials.

“The main challenge is the rapid degradation of tumor-associated antigens by serum proteases and their poor accumulation in lymphoid organs, which limits immune cell uptake and activation and hampers their ability to generate a robust anti-tumor response,” said research corresponding author Helena F. Florindo, scientist at the Research Institute for Medicines. “Our research introduced a multivalent nanoconjugate vaccine that protects tumor-associated antigens from degradation, enhances their delivery to lymph nodes, and improves dendritic cell activation, which resulted in lower expression of the suppressive PD-L1 immune checkpoint [a protein on immune cells that regulate the immune system’s response]. 

“This induced mechanism helps to overcome the issue of immune evasion and weak responses seen in conventional tumor-associated antigen-based cancer vaccines.”

The team’s vaccine utilizes a star-shaped cross-linked nanocarrier made from polyglutamate, a glutamic acid that is biodegradable, non-toxic, and non-immunogenic, conjugated with melanoma-associated peptide antigens, short amino acid sequences that are used by the body to create antibodies.

“Unlike traditional peptide vaccines, this nanoconjugate travels to lymph nodes, where their accumulation improves antigen presentation and prompts a stronger and more durable immune response,” fellow research corresponding author María J. Vicent from Prince Felipe Research Center said. “The vaccine triggers potent immune-mediated anti-tumor responses, promotes cytotoxic T-cell infiltration, and synergizes with PD-1 inhibitors to reverse immunosuppression.”

Thus far, the team’s vaccine has been evaluated using mouse proxies and murine melanoma, a widely used model in preclinical studies to investigate melanoma biology and potential therapies. 

“No human trials have been conducted yet; however, the vaccine’s efficacy has been validated in humanized mouse models that mimic human immune responses,” Florindo said. “The vaccine significantly reduced tumor growth and enhanced survival in melanoma-bearing mice. Combined with PD-1 inhibitors, the vaccine demonstrated a synergistic effect, improving T-cell infiltration and anti-tumor efficacy.”

The authors pointed out that one surprising finding was that the vaccine alone altered the tumor immune landscape, reducing PD-L1 expression and improving T-cell activation, even before it was combined with immune checkpoint inhibitors.

The team explained that the next steps to bring their vaccine to patients in the real world are to conduct preclinical toxicology studies and begin early-phase clinical trials. Manufacturing techniques will also have to be developed to scale up the production of the vaccine.

“No human trials have been conducted yet; however, the vaccine’s efficacy has been validated in humanized mouse models that mimic human immune responses,” Florindo concluded. “The vaccine remains in preclinical stages. Given the need for regulatory approvals and clinical trials, real-world applications could take several years, depending on funding and trial results.”

Reference: M. J. Vicent., H.F. Florindo., et al., Off-The-Shelf Multivalent Nanoconjugate Cancer Vaccine Rescues Host Immune Response against Melanoma., Advanced Materials (2025), DOI: 10.1002/adma.202417348

Feature image credit: National Cancer Institute on Unsplash