Immunotherapy for Melanoma, Explained

Melanoma is one of the deadliest forms of skin cancer. This is mostly because it spreads more aggressively than other skin cancers. While melanoma represents only 1% of skin cancers, it accounts for a high number of cancer deaths.

Because it can grow so quickly, melanoma is difficult to treat effectively once it has spread throughout the body to the lymph nodes or other organs.

Early-stage melanoma is usually treated with surgery to remove the cancer cells. However, treatment for more advanced cases of melanoma can include immunotherapy, which is a treatment that activates your immune system to fight the cancer cells.

Here’s what you need to know about immunotherapy for melanoma.

​How immunotherapy works with the immune system

Immunotherapy helps the body’s immune system better recognize and fight off cancer cells. Immunotherapy can work in a few different ways for melanoma:

• By boosting the overall function of the immune system to destroy cancer cells
• By using a targeted attack on specific types of cancer and immune cells, called immune checkpoint inhibitors
• With cell therapy, which uses the patient’s own tumor cells to help kickstart the immune system
• With virus therapy, which uses lab-altered viruses to attack cancer cells

Here’s a closer look at each type of immunotherapy for melanoma.

​General immunotherapy

In theory, the body’s immune system can recognize and attack cancer cells to prevent their growth. But sometimes cancer cells can grow too quickly for the immune system to keep up with, or the cells can even hide from or attack the immune system. General immunotherapy uses medications that can help improve the overall function of the immune system. For instance, interleukins are proteins that can boost the immune system so it can better recognize and attack melanoma cells. Melanoma treatment uses lab-made versions of the protein, interleukin-2 (IL-2).

IL-2s are not used as often as they once were because they can have serious side effects and typically don’t work as well as immune checkpoint inhibitors.

​Immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) are a targeted form of immunotherapy. A key way that immunotherapy works in melanoma is by “turning off” specific proteins in immune cells that stop the cells from attacking the cancer.

In a healthy person, the immune system has built-in “checkpoints” that keep immune cells from destroying healthy cells. Unfortunately, melanoma cells use those checkpoints against the body and can bind with them to allow cancer to grow. Immune checkpoint inhibitors are medicines that “turn off” those specific checkpoints, allowing the immune cells to identify the melanoma and work to destroy it.

• PD-1 inhibitors: PD-1 inhibitors target an immune cell protein called PD-1. PD-1s normally function to stop immune cells from destroying other cells. Blocking PD-1s frees up those immune cells to better fight cancerous melanoma cells. PD-1 inhibitors are called pembrolizumab (brand name: Keytruda) and nivolumab (brand name: Opdivo) and are given as IV infusions. They can only be used for melanoma that has spread and can’t be removed by surgery. They may also be used as a secondary treatment (called adjuvant) and preventive treatment to lower the risk of the cancer recurring.
• PD-L1 inhibitors: PD-L1 inhibitors, atezolizumab (brand name: Tecentriq), work the same way, by blocking the PD-L1 protein on immune cells that normally stop the cells from attacking. This type of immunotherapy can be used specifically for people who have metastasized melanoma with the BRAF gene mutation. It can be given through IV or injection.
• CLTA-4 inhibitors: This type of checkpoint inhibitor targets the CTLA-4 proteins, located on T-cells in the immune system. Used alone, CLTA-4 inhibitors are less effective and have more serious side effects than other immunotherapy medications, but may be given alongside a PD-1 inhibitor. Ipilimumab (Brand name: Yervoy) is given via IV infusion.
• LAG-3 inhibitors: LAG-3 inhibitors (called relatlimab) block the LAG-3 checkpoint protein. Relatlimab is typically given via infusion in combination with a PD-1 inhibitor called nivolumab. (Together, relatlimab and nivolumab go by the brand name Opdualag.)

Checkpoint inhibitors are a promising development in melanoma treatment. Before treatment with ICIs, the average survival rate with advanced melanoma was only six months. Now, however, survival rates have far exceeded the six-month rate.

​Tumor-infiltrating lymphocyte (TIL) therapy

T cells are a specific type of immune cell that the body uses to fight cancer. When they move into a tumor, they are called tumor-infiltrating lymphocytes (TILs). TIL therapy is a newer cancer treatment that removes TILs from a tumor, multiplies them in a lab, and returns them to the body in the form of an infusion. TIL can be effective for advanced melanoma because the T cells taken from the cancer cells have “learned” to specifically recognize melanoma.

The treatment is complex and given in several steps in the hospital. In 2024, the U.S. Food and Drug Administration (FDA) approved lifileucel (brand name: Amtagvi) as the first FDA-approved tumor-derived T-cell immunotherapy.

​Oncolytic virus therapy

Oncolytic virus therapy involves “hijacking” viruses to target cancer cells. Viruses are notorious for their ability to hide from the immune system and attack healthy cells, so scientists have discovered a way to put that power to good use by altering viruses (called oncolytic viruses) in a lab to attack cancer cells instead.

In addition to directly destroying cancer cells, oncolytic viruses can also alert the rest of the immune system to attack the cancer cells. For melanoma, talimogene laherparepvec (brand name: Imlygic), also known as T-VEC, is an oncolytic virus that can be used to try to shrink tumors that can’t be surgically removed. Currently, the primary purpose of oncolytic virus therapy in melanoma is to shrink tumor sizes, and some data show it may help increase survival rates.

Many of the immunotherapy treatment options for melanoma can be used with each other, which offers more opportunity for effective treatment. Increased immunotherapy options have offered new hope for a very challenging type of cancer.

The best outcomes from treatment always happen with earlier diagnosis, so knowing the signs of skin cancer and practicing regular skin checks is very important in the fight against melanoma.

This educational resource was created with support from Merck.