Immunotherapy for Kidney Cancer

Immunotherapy uses specialized medications to help the body's immune system recognize and attack cancer cells. For kidney cancer, the most commonly used immunotherapies are immune checkpoint inhibitors, which block molecular signals that prevent white blood cells called T cells from responding effectively to renal cell carcinoma.

Immunotherapy may be used as part of the initial treatment for advanced kidney cancer, after surgery for selected patients at increased risk of recurrence, or later if the disease returns or progresses. Depending on the cancer's stage, subtype, previous treatment history, and individual health factors, immunotherapy may be administered alone or combined with another immunotherapy or a targeted medication.

How Does Immunotherapy Work for Kidney Cancer?

The immune system uses specialized white blood cells called T cells to identify and destroy abnormal or infected cells. To prevent T cells from damaging healthy tissue, the body has checkpoint proteins that regulate when and how strongly they respond.

Cancer can take advantage of these normal checkpoints. For example, PD-L1 on tumor or immune cells can interact with PD-1 on T cells and send a signal that reduces immune activity. CTLA-4 is another checkpoint found on T cells that helps regulate their activation.

Immune checkpoint inhibitors block these interactions. Removing the inhibitory signal can help T cells remain active, recognize cancer cells as abnormal, and mount an immune response against the tumor.

Types of Immunotherapy Used for Kidney Cancer

Modern immunotherapy for renal cell carcinoma centers primarily on immune checkpoint inhibitors. The drugs are classified according to the checkpoint pathway they block.

PD-1 and PD-L1 Inhibitors

PD-1 and PD-L1 inhibitors block an interaction that can suppress T-cell activity. Drugs used in kidney cancer regimens include:

• Pembrolizumab (Keytruda®)
• Nivolumab (Opdivo®)
• Avelumab (Bavencio®)

Pembrolizumab and nivolumab may be used in several kidney cancer treatment settings. Avelumab is approved for advanced renal cell carcinoma in combination with the targeted therapy axitinib rather than as a routine single-agent treatment.

CTLA-4 Inhibitors

CTLA-4 inhibitors act at another stage of T-cell activation. Ipilimumab (Yervoy®) is the primary CTLA-4 inhibitor used in renal cell carcinoma and is commonly administered with nivolumab for selected patients with advanced disease.

Cytokine Therapy

Cytokines are immune-signaling proteins that can stimulate immune activity. Interleukin-2 and interferon-alpha were among the earliest immunotherapies used for kidney cancer.

High-dose interleukin-2 can produce durable responses in a small group of carefully selected patients, but it can also cause substantial toxicity. Its use is therefore limited to specialized centers and patients healthy enough to tolerate intensive treatment. Checkpoint inhibitors and immunotherapy-based combinations have largely replaced cytokine therapy in routine practice.

Frontline Immunotherapy Combinations for Advanced Kidney Cancer

Clinical trials have established several immunotherapy-based combinations as standard initial options for advanced renal cell carcinoma. The most appropriate regimen depends on the cancer’s histology, prognostic risk category, previous treatment, other medical conditions, and the potential side effects associated with each drug.

Dual Immunotherapy

Dual immunotherapy combines checkpoint inhibitors that affect different stages of the immune response. The primary example in kidney cancer is:

• Nivolumab plus ipilimumab

This regimen combines a PD-1 inhibitor with a CTLA-4 inhibitor. It is an established first-line option, particularly for patients with intermediate- or poor-risk advanced clear cell renal cell carcinoma.

Immunotherapy Plus Targeted Therapy

An immune checkpoint inhibitor may also be combined with a tyrosine kinase inhibitor, or TKI. TKIs block signaling pathways that contribute to cancer-cell growth and the formation of new blood vessels, while checkpoint inhibitors strengthen the immune response against the cancer.

Approved combinations for advanced kidney cancer include:

• Pembrolizumab plus axitinib
• Pembrolizumab plus lenvatinib
• Nivolumab plus cabozantinib
• Avelumab plus axitinib

These regimens have different dosing schedules, potential benefits, and side-effect profiles. Medical oncologists select treatment after considering the patient’s diagnosis, kidney function, cardiovascular health, autoimmune history, current medications, and personal treatment goals.

Who May Receive Kidney Cancer Immunotherapy?

Eligibility depends on the cancer’s stage, histologic subtype, previous treatment, surgical findings, risk of recurrence, overall health, and whether a patient has a condition that could make immune activation more hazardous.

Unresectable or Metastatic Clear Cell Kidney Cancer

Immunotherapy-based combinations are commonly used as initial systemic treatment when clear cell renal cell carcinoma cannot be removed surgically or has spread to distant areas of the body.

The choice between dual immunotherapy and an immunotherapy-TKI combination depends on several factors, including the patient’s prognostic risk group, the pace and location of the disease, symptoms, and other medical conditions.

Non-Clear Cell Renal Cell Carcinoma

Immunotherapy may also be considered for non-clear cell kidney cancers, but these tumors include several biologically distinct subtypes. The evidence supporting a particular regimen is generally less extensive than it is for clear cell RCC.

Treatment is selected according to the specific histology, and participation in a clinical trial may be recommended when an appropriate study is available. Current trials continue to evaluate immunotherapy combinations for papillary RCC and other less common kidney cancer subtypes.

Adjuvant Therapy After Nephrectomy

Selected patients with renal cell carcinoma containing a clear cell component may receive systemic treatment after surgery if the cancer carries an intermediate-high or high risk of returning.

Pembrolizumab may be administered for up to one year after nephrectomy to reduce recurrence risk. In June 2026, the FDA also approved belzutifan in combination with pembrolizumab for adults with clear cell RCC at intermediate-high or high risk of recurrence following nephrectomy, including selected patients who also had metastatic lesions removed.

The decision to recommend adjuvant treatment depends on the tumor’s stage and grade, lymph-node involvement, whether metastatic disease was completely removed, overall health, and the potential risks of treatment.

Recurrent or Previously Treated Kidney Cancer

Immunotherapy may be used later in treatment for someone who has not already received a checkpoint inhibitor. Nivolumab, for example, is an established option after certain VEGF-targeted therapies.

Many patients now receive immunotherapy during first-line treatment, however. If the cancer later progresses, the next therapy is selected according to the drugs already received, the duration of response, tumor characteristics, remaining kidney function, and the patient’s overall condition.

How Effective Is Immunotherapy for Kidney Cancer?

Immunotherapy has become an important part of treatment for advanced renal cell carcinoma, but individual responses vary. Some tumors shrink substantially, some remain stable for a period of time, and others do not respond.

A smaller group of patients experience long-lasting responses, including complete disappearance of detectable cancer. Researchers continue to study tumor characteristics, immune markers, and other factors that may help predict who is most likely to benefit. No single immunotherapy regimen is appropriate for every person with kidney cancer.

Potential Side Effects and Immune-Related Adverse Events

Immunotherapy side effects differ from those caused by chemotherapy or targeted therapy. By increasing immune activity, checkpoint inhibitors can sometimes cause the immune system to inflame healthy organs and tissues. These immune-related adverse events can range from mild to serious and may occur during treatment or after treatment has ended.

Early reporting is important because some reactions can worsen without treatment.

Common Side Effects

Potential side effects include:

• Fatigue or weakness
• Skin rash, itching, or dryness
• Diarrhea
• Reduced appetite
• Nausea
• Joint or muscle discomfort
• Mild fever or chills
• Infusion-related reactions

Potentially Serious Immune-Related Reactions

Immune-related inflammation can affect almost any part of the body. Examples include:

• Pneumonitis: Lung inflammation that may cause a new or worsening cough, chest discomfort, or shortness of breath
• Colitis: Intestinal inflammation that may cause frequent diarrhea, abdominal pain, or blood in the stool
• Hepatitis: Liver inflammation that may cause abnormal blood-test results, yellowing of the skin, dark urine, or abdominal discomfort
• Endocrine disorders: Inflammation affecting the thyroid, pituitary, adrenal glands, or pancreas, which can alter hormone levels
• Nephritis: Kidney inflammation that may reduce kidney function
• Myocarditis: Inflammation of the heart muscle
• Neurologic reactions: Weakness, numbness, confusion, or other nervous-system symptoms

Some immune-related reactions are uncommon but can become life-threatening. Patients should contact their care team promptly about any new, persistent, or rapidly worsening symptom rather than waiting until the next scheduled appointment.

Side Effects of Immunotherapy-TKI Combinations

When immunotherapy is combined with a TKI, patients may also experience effects associated with the targeted medication. Depending on the drug, these can include:

• High blood pressure
• Diarrhea
• Fatigue
• Mouth irritation
• Liver-test abnormalities
• Changes in thyroid function
• Hand-foot skin reactions
• Reduced appetite or weight loss

Because symptoms may be caused by the immunotherapy, the TKI, the cancer itself, or another health condition, patients should report changes promptly so the team can determine the most appropriate response.

How Side Effects Are Managed

Before and during treatment, the care team may monitor symptoms, blood counts, kidney and liver function, thyroid function, and other hormone levels.

Management depends on the organ involved and the severity of the reaction. It may include:

• Close monitoring for a mild reaction
• Temporarily pausing one or more medications
• Permanently stopping treatment after certain serious reactions
• Corticosteroids or other immune-suppressing medications
• Hormone-replacement therapy for some endocrine complications
• Referral to another specialist when a specific organ is affected

Patients should not attempt to treat suspected immune-related effects or stop prescribed medication without contacting their oncology team.

How Immunotherapy Fits into Kidney Cancer Care

Immunotherapy may be given alone or combined with targeted therapy, surgery, radiation therapy, or other approaches as part of an individualized kidney cancer treatment plan.

Surgery

Partial or radical nephrectomy remains the primary treatment for most localized kidney cancers. In metastatic disease, removing the primary kidney tumor may benefit selected patients, but the decision and timing depend on the extent of disease, symptoms, prognostic risk, and response to systemic treatment. Moffitt offers several surgical options for kidney cancer, including partial nephrectomy, radical nephrectomy, and minimally invasive techniques when appropriate.

Researchers continue to study whether immunotherapy should be given before or after cytoreductive nephrectomy in different groups of patients with metastatic disease.

Targeted Therapy

Targeted therapy for kidney cancer uses medications that interfere with molecular pathways renal cell carcinomas rely on to grow and form new blood vessels. These drugs may be combined with immunotherapy as an initial treatment for advanced disease or used later if the cancer progresses.

Radiation Therapy

Although radiation therapy for kidney cancer is not usually the primary treatment for a localized renal cell tumor, it may be used to relieve symptoms or control cancer that has spread to areas such as the bones or brain. Clinical trials are also studying whether radiation can strengthen the effects of immunotherapy in selected patients with unresectable or metastatic disease.

Ablation and Interventional Procedures

For selected patients with small, localized kidney tumors, kidney tumor ablation may provide an alternative when surgery is not the preferred option. Image-guided procedures such as cryoablation and radiofrequency ablation destroy tumor tissue using extreme cold or heat.

These procedures are not routinely paired with immunotherapy, but they may be included in a broader treatment strategy based on the number, size, and location of the tumors.

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Moffitt’s approach to kidney cancer immunotherapy

Moffitt Cancer Center’s Urologic Oncology Program has a renowned kidney cancer team that comprises physicians from multiple specialties who collaborate to develop an individualized treatment plan for every patient. This is especially important for treatment options like immunotherapy, which are often integrated alongside other therapies and require an experienced team to manage possible treatment-related side effects. A multispecialty approach ensures that patients are able to see the best possible outcomes and experience a high quality of life.

Moffitt is known for its groundbreaking research and robust clinical trials program, which includes immunotherapy options for the treatment of kidney cancer. These efforts, along with our comprehensive clinical treatment and supportive care, have earned us designation as a Comprehensive Cancer Center by the National Cancer Institute.

To learn more about how immunotherapy is used for treating kidney cancer or to consult with an oncologist specializing in the treatment of kidney cancer, contact Moffitt by calling 1-888-663-3488, or complete a new patient registration form online. Referrals are not required to visit Moffitt.

References

• Immune Checkpoint Inhibitors - NCI
• Treating Kidney Cancer | American Cancer Society
• FDA Approves Belzutifan With Pembrolizumab for Adjuvant Treatment of Renal Cell Carcinoma | FDA