Immunotherapy vs Chemotherapy for Cancer: Key Differences

Research-informed explainer — last updated 2026-04-11

Immunotherapy and chemotherapy are both used to treat cancer, but they work in opposite ways and are not interchangeable. For certain cancers and certain patients, immunotherapy now produces survival results that chemotherapy simply cannot match. For others, chemotherapy remains the standard or the two are combined.

This explainer draws on peer-reviewed research from three oncologists listed in the Convene directory. Their published work spans the landmark clinical trials that reshaped how advanced melanoma, lung cancer, and kidney cancer are treated.

What is chemotherapy?

Chemotherapy uses drugs that kill cells which divide quickly. Cancer cells divide faster than most normal cells, so they take a disproportionate hit. The problem is that some healthy cells also divide quickly: the lining of the gut, hair follicles, bone marrow. That is why chemotherapy causes side effects like nausea, hair loss, and low blood counts. The drugs move through the bloodstream and attack dividing cells throughout the body.

Chemotherapy has been in use for decades. It can shrink tumors, slow growth, and in some cases cure cancer. But for many advanced solid tumors, the responses have historically been short-lived. The disease often finds a way to keep growing.

What is immunotherapy?

Immunotherapy works differently. Instead of attacking cancer cells directly, it works on your immune system. Immune checkpoint inhibitors, the class of drugs that has reshaped oncology over the past decade, release a brake that cancer cells have been using to hide from your immune system. Two proteins, PD-1 and CTLA-4, normally help the immune system avoid attacking healthy tissue. Many cancers exploit these proteins to look "safe" to immune cells. Drugs like pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy) block those proteins and allow immune T-cells to recognize and attack the tumor.

The immune response, once activated, can persist long after treatment ends. That durability is what separates immunotherapy from chemotherapy.

At a glance

What biomarker testing tells you

Before recommending immunotherapy, oncologists test the tumor for specific markers. PD-L1 expression measures how much of the target protein is on tumor cells. Tumor mutational burden (TMB) measures how many genetic mutations the tumor carries. Tumors with more mutations tend to produce more abnormal proteins, giving the immune system more targets to recognize.

A 2012 study in the New England Journal of Medicine, part of the foundational research that established the PD-1 pathway as a treatment target, found that patients with PD-L1 expression on their tumor cells were more likely to respond to anti-PD-1 therapy [5]. Those findings eventually shaped the testing protocols now used before starting checkpoint inhibitors. If your oncologist orders a biopsy with special staining or a next-generation sequencing panel before recommending a treatment, this is what they are looking for.

What the trials showed in melanoma

Metastatic melanoma was once one of the most treatment-resistant cancers. Chemotherapy with dacarbazine was the standard for decades, with median survival around nine months and almost no long-term survivors.

An early trial showed that combining ipilimumab (a CTLA-4 inhibitor) with dacarbazine improved overall survival versus dacarbazine alone. Three-year survival was 20.8% in the combination group versus 12.2% with chemotherapy, a 28% reduction in the risk of death [2]. It was a real improvement, though most patients still did not survive long-term.

Researchers then tested two checkpoint inhibitors together. A 2013 study in the New England Journal of Medicine combined nivolumab and ipilimumab and found rapid, deep tumor regression in a substantial portion of patients, with responses that looked different from anything seen with single-agent treatment [3]. That early-phase signal led to the CheckMate 067 trial.

CheckMate 067 was a large randomized trial comparing three regimens: nivolumab plus ipilimumab, nivolumab alone, and ipilimumab alone. The combination arm produced a median progression-free survival of 11.5 months, compared to 2.9 months for ipilimumab and 6.9 months for nivolumab alone [1].

The most consequential data came five years later. A 2019 report in the New England Journal of Medicine on the same trial's long-term outcomes found that 52% of patients who received nivolumab plus ipilimumab were alive at five years, compared to 26% for ipilimumab alone. Median overall survival for the combination group was 60 months, at a time when dacarbazine chemotherapy produced a median survival under a year [4]. Those numbers — 52% alive at five years versus near-zero with dacarbazine — are not incremental gains. They are a different category of result.

The trade-off is toxicity. Serious immune-related adverse events (grade 3 or 4) occurred in about 55% of patients on the combination in CheckMate 067, compared to roughly 27% for ipilimumab alone and 16% for nivolumab alone. Combination immunotherapy requires close monitoring by an experienced oncologist.

What the trials showed in lung cancer

Lung cancer is the most common cause of cancer death in the United States. For most of its history, treatment was cisplatin-based chemotherapy, and survival for advanced non-small-cell lung cancer (NSCLC) was measured in months, not years.

The KEYNOTE-024 trial was a turning point for patients with high PD-L1 expression. This 2016 study in the New England Journal of Medicine compared pembrolizumab to platinum-doublet chemotherapy as first-line treatment for NSCLC patients whose tumors expressed PD-L1 on at least 50% of cells. Pembrolizumab cut the risk of disease progression or death in half compared to chemotherapy (hazard ratio 0.50). Median progression-free survival was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy. Response rates were 44.8% versus 27.8%, and responses to pembrolizumab lasted much longer [6]. Severe adverse events occurred in 26.6% of the pembrolizumab group compared to 53.3% in the chemotherapy group.

For patients whose tumors carry a high tumor mutational burden, a different combination, nivolumab plus ipilimumab, also outperformed chemotherapy. A 2018 trial in the New England Journal of Medicine showed significantly longer progression-free survival with dual checkpoint blockade versus chemotherapy in high-TMB lung cancer, and the benefit held regardless of PD-L1 expression levels [7].

For a patient with newly diagnosed advanced NSCLC today, the first question is now about biomarkers, not which chemotherapy drugs to use. PD-L1 testing and TMB testing directly determine whether immunotherapy is likely to work.

What the trials showed in kidney cancer

Advanced kidney cancer (renal cell carcinoma, or RCC) was historically resistant to both chemotherapy and radiation. Targeted therapies, drugs that block the signals cancer cells use to grow, replaced chemotherapy as the standard, but responses were still not durable for most patients.

Immunotherapy moved in. The CheckMate 025 trial compared nivolumab to everolimus (a targeted therapy) as second-line treatment after prior therapy. Nivolumab produced a median overall survival of 25.0 months versus 19.6 months for everolimus, a 27% reduction in the risk of death. The objective response rate was 25% with nivolumab versus 5% with everolimus. Serious adverse events were also less common with nivolumab [8].

For first-line treatment, the CheckMate 214 trial compared nivolumab plus ipilimumab to sunitinib (the prior targeted-therapy standard) in patients with intermediate- or poor-risk advanced RCC. Eighteen-month overall survival was 75% with the combination versus 60% with sunitinib. The objective response rate was 42% versus 27%, and 9% of patients on the combination had a complete response, compared to 1% on sunitinib [9].

A combination of avelumab plus axitinib, pairing immunotherapy with a targeted agent, also outperformed sunitinib in progression-free survival as first-line treatment [10].

For kidney cancer patients being treated today, the question is not immunotherapy or chemotherapy (chemotherapy was largely abandoned for RCC years ago). It is which immunotherapy-based regimen fits the patient's risk profile and biomarkers.

When chemotherapy is still the right choice

Immunotherapy is not right for everyone. For many colon cancers, pancreatic cancers, and some breast cancers, the tumor lacks the biomarkers that predict a checkpoint inhibitor response, and chemotherapy remains standard. Some patients have autoimmune conditions that make immune-activating drugs dangerous. In other situations, chemotherapy is given alongside immunotherapy rather than replaced by it.

For some cancers, immunotherapy is still in clinical trials rather than standard care. Your oncologist will look at the tumor type, specific biomarkers, overall health, and prior treatment history before recommending a regimen.

The field is also moving quickly. Guidelines are updated as new trial data comes in. What was standard care in 2020 may not be in 2026.

Side effects: what to expect from each

Chemotherapy and immunotherapy have different side effect profiles, and the difference matters for how you plan daily life during treatment.

Chemotherapy side effects are fairly predictable. Nausea usually peaks in the first few days after each cycle. Hair loss typically starts a few weeks in and grows back after treatment ends. Fatigue and low blood counts are common and require regular lab monitoring.

Immunotherapy side effects are less predictable. Because the drugs activate the immune system, they can cause inflammation in almost any organ: the lungs (pneumonitis), the gut (colitis), the liver (hepatitis), the skin, the joints, the thyroid, and sometimes the heart or nervous system. These reactions can appear weeks or even months after starting treatment. Most are manageable with corticosteroids if caught early, but they can become serious if ignored.

If you are on immunotherapy and notice new shortness of breath, persistent diarrhea, jaundice, or severe joint pain, tell your oncologist the same day. Do not wait for the next scheduled visit.

Questions to ask your oncologist

• Has my tumor been tested for PD-L1 expression and tumor mutational burden?
• Is immunotherapy, chemotherapy, or a combination recommended for my specific cancer type and stage?
• Which clinical trials are open to me, and are any of them worth considering before standard treatment?
• If I start immunotherapy, how often will I be monitored for immune-related side effects?
• What is the expected response rate and duration of response for my tumor profile?
• If the first-line treatment stops working, what are the next options?

The bottom line

For advanced melanoma, PD-L1-positive lung cancer, and kidney cancer, immunotherapy has largely replaced or superseded chemotherapy as first-line treatment. The survival gains in the landmark trials are substantial and durable in ways chemotherapy could not match. But immunotherapy only works when the tumor has the right characteristics, and it carries a distinct set of risks that require experienced monitoring.

The answer to "which is better" depends on your tumor type, biomarker results, and overall health. Bring the questions above to your oncologist. The choice is not immunotherapy versus chemotherapy in the abstract. It is the right treatment for your specific cancer.