Why does immunotherapy cause side effects?
The National Cancer Institute gives one reason. Side effects happen when the immune system that is revved up to act against the cancer also acts against healthy cells and tissues in the body.
That is the whole mechanism. What follows from it explains why these drugs behave so differently from chemotherapy.
The brakes, and what happens when they come off
The immune system has built-in checkpoints. NCI describes them as a normal part of it, there to prevent an immune response from being so strong that it destroys healthy cells.
Checkpoints work through pairs of proteins. When a checkpoint protein binds its partner, an "off" signal goes to the T cells. Some tumors abuse this: NCI says some turn down the T cell response by producing lots of PD-L1.
Checkpoint inhibitors block that binding, so the "off" signal is never sent and T cells can kill cancer cells. One class acts against a checkpoint protein called CTLA-4. Others act against PD-1 or its partner PD-L1.
Here is the catch. The brake being released is not tumor-specific. It is the same brake that restrains T cells elsewhere in the body.
Which is why the side effects are named after organs
Chemotherapy harms fast-dividing cells, which is why hair and blood counts suffer. Checkpoint inhibitors cause inflammation, and NCI lists the rarer effects by the organ inflamed.
- Skin: changes in skin color, rash, and itching.
- Lungs: cough and chest pain.
- Colon: belly pain and diarrhea.
- Pancreas: diabetes.
- Liver: hepatitis.
- Pituitary gland: hypophysitis.
- Heart muscle: myocarditis.
- Kidney: nephritis, with impaired kidney function.
- Thyroid: an overactive or underactive gland.
- Nervous system: muscle weakness, numbness, and trouble breathing.
The common ones are milder and more familiar: rash, diarrhea, and fatigue.
Across all types of immunotherapy, NCI also lists needle-site reactions such as pain, swelling, soreness, redness, itchiness, and rash, and flu-like symptoms including fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint aches, fatigue, headache, trouble breathing, and low or high blood pressure. Other effects include fluid retention with swelling and weight gain, heart palpitations, sinus congestion, diarrhea, infection, and organ inflammation. NCI notes that severe or fatal allergic and inflammation-related reactions can occur with some types, but that these are rare.
The timing rule that sets these drugs apart
NCI states it plainly: side effects can occur at any point during and after treatment. Treatment itself may last a long time.
That matters practically. A cough or persistent diarrhea months after the last dose can still be related. Chemotherapy side effects generally fade on a predictable schedule; these do not.
NCI is also honest that doctors and nurses cannot know for certain when or whether side effects will occur, or how serious they will be. Which is why it says it is important to know which signs to look for and what to do.
What to do with this
Report symptoms early, while they are small.
Ask the team, before the first dose, which symptoms warrant a phone call and which warrant the emergency room. Get the after-hours number and keep it in a phone.
On fever, two federal pages disagree. NCI's infection page lists a "fever of 100.5 °F (38 °C) or higher," but 38 °C is actually 100.4 °F. MedlinePlus, reviewed in October 2024, uses 100.4 °F (38 °C). The more recent page is also the internally consistent one, and the treating team's own threshold overrides both.
Other reasons to call: new or worsening diarrhea, shortness of breath, chest pain, yellowing of the skin or eyes, or a rash that is spreading or blistering.
Finally, tell every clinician about the immunotherapy, including urgent care and emergency staff, and name the drug. An immune reaction is managed differently from an ordinary infection. Our guide to immunotherapy side effects: when to call the doctor covers the thresholds, and immunotherapy colitis and severe diarrhea covers the most common serious one.
NCI's immunotherapy side effects page was reviewed on February 16, 2023, and its checkpoint inhibitor page on April 7, 2022.
Sources
Want the full picture? Read our complete explanation: What Is Immunotherapy? Cancer and the Immune System
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