Immunotherapy: A Comprehensive Treatment Guide

How Immunotherapy Works

The immune system constantly patrols the body for abnormal cells. White blood cells called T cells are particularly important in this surveillance. When T cells encounter a foreign or abnormal cell, they can mount an attack to destroy it. Under normal circumstances, the immune system is capable of identifying and eliminating many early cancer cells before they form tumors.

However, cancer cells develop ways to evade immune detection. Some cancer cells produce proteins that act as “brakes” on T cells, effectively telling the immune system to stand down. Others disguise themselves to look like normal cells, or they create a microenvironment around the tumor that suppresses immune activity. Immunotherapy works by counteracting these evasion strategies, essentially removing the brakes or providing the immune system with better tools to find and fight cancer.

Unlike chemotherapy, which directly kills rapidly dividing cells, immunotherapy empowers the body's own defense system. This fundamental difference explains why immunotherapy can sometimes produce remarkably durable responses — once the immune system learns to recognize cancer cells, that recognition can persist long after treatment ends, a phenomenon sometimes called immune memory.

Checkpoint Proteins and Immune Evasion

Immune checkpoints are regulatory molecules on the surface of T cells and other immune cells. Under normal conditions, these checkpoints prevent the immune system from attacking healthy tissue. Cancer cells exploit this system by expressing checkpoint ligands that bind to T cell checkpoint receptors, sending an inhibitory signal that deactivates the T cell. The most important checkpoint pathways in cancer treatment are PD-1/PD-L1 and CTLA-4.

The PD-1 (programmed death-1) receptor sits on the surface of T cells. When PD-L1 (programmed death-ligand 1) on the cancer cell binds to PD-1, it sends a “don't attack” signal. CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is another checkpoint receptor that downregulates T cell activation at an earlier stage, during the initial priming phase in lymph nodes.

Types of Immunotherapy

Checkpoint Inhibitors

Checkpoint inhibitors are monoclonal antibodies that block checkpoint proteins, releasing the brakes on the immune system. They are the most broadly used immunotherapy class and have transformed outcomes in many cancer types.

PD-1 Inhibitors

Pembrolizumab (Keytruda) is the most widely prescribed checkpoint inhibitor, approved for more than 20 cancer types including non-small cell lung cancer, triple-negative breast cancer, melanoma, bladder cancer, renal cell carcinoma, and any MSI-H/dMMR solid tumor. Nivolumab (Opdivo) is approved for melanoma, lung cancer, kidney cancer, hepatocellular carcinoma, esophageal cancer, and several other indications. Cemiplimab (Libtayo) is used for advanced cutaneous squamous cell carcinoma and lung cancer.

PD-L1 Inhibitors

Atezolizumab (Tecentriq) is approved for lung cancer, bladder cancer, liver cancer, and certain breast cancers. Durvalumab (Imfinzi) is used after chemoradiation in stage III lung cancer and for bladder cancer. Avelumab (Bavencio) is approved for Merkel cell carcinoma and advanced urothelial carcinoma, notably as a maintenance therapy.

CTLA-4 Inhibitors

Ipilimumab (Yervoy) was the first checkpoint inhibitor approved (2011, for melanoma) and works by blocking CTLA-4, enhancing T cell activation during the priming phase. It is frequently combined with nivolumab for melanoma, kidney cancer, MSI-H colorectal cancer, liver cancer, and mesothelioma. The combination targets two different checkpoints for a more robust immune response.

CAR-T Cell Therapy

Chimeric antigen receptor T cell (CAR-T) therapy is a personalized treatment in which a patient’s T cells are extracted, genetically engineered to recognize a specific protein on cancer cells, then multiplied in a laboratory and infused back into the patient. Currently approved CAR-T products (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, idecabtagene vicleucel, ciltacabtagene autoleucel) target CD19 on B-cell lymphomas and leukemias or BCMA on multiple myeloma.

CAR-T therapy can produce complete remissions in patients who have failed multiple prior treatments. However, it carries significant risks including cytokine release syndrome (CRS) — a potentially life-threatening inflammatory reaction — and neurotoxicity (ICANS). Patients require close monitoring in specialized treatment centers.

Cancer Vaccines

Therapeutic cancer vaccines aim to stimulate the immune system to attack existing cancer. Sipuleucel-T (Provenge) is approved for metastatic prostate cancer. Unlike preventive vaccines (such as HPV vaccines, which prevent cancer from developing), therapeutic vaccines treat cancer that is already present. Research is advancing in personalized neoantigen vaccines, which are custom-designed based on the unique mutations in a patient’s tumor.

Cytokines

Cytokines are signaling proteins that boost immune activity. Interleukin-2 (IL-2, aldesleukin) can produce durable complete responses in melanoma and kidney cancer, but its severe side effects limit use. Interferon-alpha was historically used for melanoma and kidney cancer but has largely been replaced by checkpoint inhibitors.

Bispecific Antibodies

Bispecific antibodies are engineered molecules that simultaneously bind to a cancer cell and a T cell, bringing them into close proximity to facilitate killing. Blinatumomab (Blincyto), targeting CD19 and CD3, is approved for B-cell acute lymphoblastic leukemia. Newer bispecific antibodies are being developed for solid tumors and other hematologic malignancies, including teclistamab for multiple myeloma and epcoritamab for diffuse large B-cell lymphoma.

Biomarkers That Predict Response

Not all patients respond to immunotherapy. Biomarker testing helps oncologists identify who is most likely to benefit, guiding treatment decisions and avoiding unnecessary side effects in patients unlikely to respond.

PD-L1 Expression

Immunohistochemistry (IHC) testing measures how much PD-L1 protein is present on tumor cells or immune cells within the tumor. Higher PD-L1 expression generally correlates with better response to PD-1/PD-L1 inhibitors, though some PD-L1–negative patients also respond. Different cancers use different PD-L1 scoring systems (Tumor Proportion Score, Combined Positive Score), and thresholds for treatment eligibility vary by cancer type and drug.

Microsatellite Instability (MSI-H) and Mismatch Repair Deficiency (dMMR)

Tumors with defective DNA mismatch repair accumulate many mutations, producing numerous abnormal proteins (neoantigens) that the immune system can recognize. MSI-H/dMMR tumors respond exceptionally well to checkpoint inhibitors. Pembrolizumab has a tissue-agnostic approval for any MSI-H/dMMR solid tumor — the first cancer approval based on a biomarker rather than tumor location. MSI-H status is most common in colorectal cancer, endometrial cancer, and gastric cancer.

Tumor Mutational Burden (TMB)

TMB measures the total number of mutations in a tumor’s DNA. Tumors with high TMB (TMB-H, generally defined as ≥10 mutations per megabase) tend to produce more neoantigens and may respond better to checkpoint inhibitors. Pembrolizumab has a tissue-agnostic approval for TMB-H solid tumors. TMB is typically measured through next-generation sequencing (NGS) of tumor tissue or liquid biopsy.

Which Cancers Respond Best

Immunotherapy has become a standard treatment component for many cancers, though response rates vary significantly. Cancers with high mutational burden or strong immune infiltration tend to respond best.

• Melanoma: One of the first cancers where immunotherapy showed dramatic results. Combination nivolumab plus ipilimumab produces five-year survival rates exceeding 50% in advanced melanoma
• Non-small cell lung cancer: Pembrolizumab alone or combined with chemotherapy is a first-line standard. High PD-L1 expressors (≥50%) can achieve particularly strong responses
• Kidney cancer: Combination immunotherapy (nivolumab + ipilimumab or checkpoint inhibitor + TKI) has become the standard first-line treatment for advanced disease
• Bladder cancer: Multiple checkpoint inhibitors are approved. Avelumab maintenance after platinum chemotherapy improves overall survival
• MSI-H/dMMR cancers: Regardless of tumor type, MSI-H tumors show high response rates to checkpoint inhibitors
• Liver cancer: Atezolizumab plus bevacizumab is the first-line standard for unresectable hepatocellular carcinoma

Immune-Related Adverse Events (irAEs)

Because immunotherapy activates the immune system broadly, it can cause the immune system to attack healthy organs and tissues. These immune-related adverse events (irAEs) differ fundamentally from chemotherapy side effects and require different management approaches. irAEs can affect virtually any organ system but most commonly involve the skin, gastrointestinal tract, liver, lungs, and endocrine glands.

Common irAEs

• Skin: Rash, itching (pruritus), and vitiligo are among the most frequent irAEs, occurring in 30–40% of patients
• Colitis: Diarrhea and inflammation of the colon, more common with CTLA-4 inhibitors and combination regimens
• Hepatitis: Elevated liver enzymes indicating liver inflammation; monitored through regular blood tests
• Pneumonitis: Inflammation of the lungs causing cough and shortness of breath; requires prompt treatment
• Endocrinopathies: Thyroid dysfunction (hypothyroidism or hyperthyroidism), adrenal insufficiency, hypophysitis (inflammation of the pituitary gland), and type 1 diabetes
• Fatigue: Very common but can also indicate underlying endocrine irAE

Combination Strategies

Immunotherapy is increasingly used in combination with other treatments to improve outcomes:

• Immunotherapy + immunotherapy: Nivolumab plus ipilimumab (dual checkpoint blockade) for melanoma, kidney cancer, and MSI-H colorectal cancer
• Immunotherapy + chemotherapy: Pembrolizumab plus platinum-based chemotherapy is standard first-line treatment for many lung cancers
• Immunotherapy + targeted therapy: Checkpoint inhibitors combined with VEGF-targeting agents for kidney and liver cancer
• Immunotherapy + radiation therapy: Durvalumab after chemoradiation for stage III lung cancer; radiation may also enhance immunotherapy response through the abscopal effect

Practical Considerations for Patients

Immunotherapy is typically administered as an intravenous infusion every two to six weeks, depending on the drug and schedule. Treatment duration varies — many protocols continue for up to two years or until disease progression. Some patients who achieve a complete response may stop treatment earlier under careful monitoring.

Unlike chemotherapy, immunotherapy does not typically cause hair loss, severe nausea, or neutropenia. However, patients must remain vigilant for irAE symptoms, which can develop at any time during treatment or even months after stopping. Regular blood tests to monitor liver function, thyroid function, and other organ markers are essential throughout treatment.

Patients should discuss autoimmune disease history with their oncologist, as pre-existing autoimmune conditions may increase irAE risk. Organ transplant recipients require special consideration due to the risk of graft rejection with immune activation.

Last reviewed: March 2026. This information is for educational purposes only and is not a substitute for professional medical advice. Always consult your oncologist about your specific treatment plan.