Immunotherapy is not a last resort. While it was originally approved for cancers that had stopped responding to other treatments, it has moved to the front of the line for several major cancer types. In metastatic melanoma and many forms of non-small-cell lung cancer, immunotherapy is now the standard first-line treatment, meaning it’s the first thing oncologists reach for, not a backup plan.
That said, the answer depends on your specific cancer type, its molecular profile, and how advanced it is. For some cancers, immunotherapy still plays a later-line role. Understanding where it fits in your treatment plan starts with understanding how it works differently from older therapies.
How Immunotherapy Differs From Chemotherapy
Chemotherapy works by killing fast-dividing cells directly. It’s effective but indiscriminate, which is why it causes side effects like hair loss and nausea. Immunotherapy takes a fundamentally different approach: instead of attacking cancer cells itself, it removes the brakes on your immune system so your own T cells can recognize and destroy the tumor.
Cancer cells often survive by hijacking “checkpoint” signals that tell immune cells to stand down. Checkpoint inhibitors, the most common type of immunotherapy, block those signals and restore your immune system’s ability to fight back. This distinction matters because immunotherapy can produce durable, long-lasting responses in some patients. When it works, the immune system essentially learns to keep the cancer in check, sometimes for years after treatment ends.
Cancers Where Immunotherapy Comes First
For several cancer types, national treatment guidelines now list immunotherapy as the preferred first option:
- Metastatic melanoma: Checkpoint inhibitors are the standard first-line treatment regardless of certain genetic mutation status.
- Non-small-cell lung cancer (NSCLC): Patients whose tumors express a protein called PD-L1 on at least 50% of their cells can receive immunotherapy alone as their initial treatment. In 2019, the FDA expanded this to patients with PD-L1 levels as low as 1%. For patients with little or no PD-L1 expression, immunotherapy combined with chemotherapy is still first-line.
- Advanced kidney cancer: Combinations of two immunotherapy drugs, or immunotherapy paired with a targeted therapy, are standard initial treatments for intermediate and poor-risk cases.
- Head and neck squamous cell carcinoma: Immunotherapy alone or with chemotherapy is a first-line option for recurrent or metastatic disease when tumors express PD-L1.
- Small-cell lung cancer: Immunotherapy combined with chemotherapy is the initial treatment for extensive-stage disease.
- Merkel cell carcinoma: Immunotherapy is a first-line option for recurrent, locally advanced, or metastatic cases in both adults and children.
This list continues to grow. A decade ago, none of these cancers had immunotherapy as a first choice.
When Immunotherapy Is Used After Surgery
Immunotherapy isn’t limited to advanced cancer. It’s increasingly used before or after surgery to reduce the chance of cancer coming back. Treatment given before surgery (neoadjuvant therapy) can shrink tumors and make them easier to remove, while also potentially training the immune system to hunt down remaining cancer cells. Treatment given after surgery (adjuvant therapy) targets microscopic disease that might still be present.
In one landmark study of stage II and III lung cancer patients, immunotherapy given after surgery and chemotherapy reduced the risk of the cancer returning or the patient dying by 34% among those whose tumors expressed PD-L1. Even when researchers looked at all patients regardless of PD-L1 levels, the risk dropped by 21%. These are patients with earlier-stage, operable cancer, far from a “last resort” scenario.
Where Immunotherapy Still Plays a Later Role
For certain cancers, immunotherapy remains a second-line or later option. Some examples of when it’s used after other treatments have been tried:
CAR T-cell therapy, a specialized form of immunotherapy that engineers a patient’s own immune cells to attack cancer, is approved for blood cancers like acute lymphoblastic leukemia and large B-cell lymphomas specifically in patients whose disease has relapsed or resisted multiple prior treatments. This is genuinely a later-line therapy. Similarly, for some solid tumors like certain gastrointestinal cancers and bladder cancer, immunotherapy is approved as a treatment after the disease has progressed on standard chemotherapy, or when standard treatment isn’t feasible.
Immunotherapy can also serve as an alternative for patients who can’t tolerate conventional treatments, such as elderly patients who may not be candidates for aggressive chemotherapy. In these cases, it’s not so much a last resort as a better-tolerated option.
Biomarkers That Determine Eligibility
Whether immunotherapy is offered first or later often depends on specific biological markers in your tumor. The most important ones:
- PD-L1 expression: Measures how much of a checkpoint protein your tumor displays. Higher levels generally predict a better response to checkpoint inhibitors. In lung cancer, PD-L1 of 50% or higher qualifies you for immunotherapy alone as a first treatment.
- MSI-H/dMMR: Tumors with a specific DNA repair deficiency (called microsatellite instability-high) tend to respond well to immunotherapy. This marker qualifies patients for immunotherapy across all solid tumor types, regardless of where the cancer originated.
- Tumor mutational burden (TMB): Cancers with 10 or more mutations per megabase of DNA are classified as TMB-high and may qualify for immunotherapy. This benefit extends beyond MSI-H tumors, since most TMB-high cancers in key clinical trials were actually microsatellite stable.
Your oncologist will typically test for these markers when you’re first diagnosed. The results can shift immunotherapy from a later option to a first-line treatment, or vice versa.
What Treatment Looks Like
Immunotherapy drugs are generally given as intravenous infusions in cycles ranging from every 2 to 6 weeks. For metastatic cancer, treatment can continue for up to 2 years. For adjuvant or neoadjuvant use, courses are shorter, typically 1 month to 1 year.
Side effects are different from chemotherapy. Because immunotherapy activates the immune system broadly, it can trigger inflammation in healthy organs. Skin reactions, thyroid problems, gut inflammation, and joint pain are among the more common issues. Most are mild and manageable, but moderate or severe reactions may require pausing treatment temporarily. In many cases, treatment can be restarted once symptoms improve, particularly if the side effects respond to treatment and remain controlled.
The Bigger Picture
The idea that immunotherapy is a last resort reflects where the field was roughly a decade ago, when early approvals were limited to cancers that had failed everything else. That’s no longer the reality. For melanoma, lung cancer, kidney cancer, and a growing list of other tumor types, immunotherapy is the first and often the best option. For cancers with favorable biomarkers like MSI-H or high TMB, it can be effective regardless of where the tumor originated. The treatment continues to move earlier in the cancer journey, from metastatic disease to post-surgical prevention to pre-surgical tumor shrinkage. Where it fits for any individual patient depends on cancer type, stage, and molecular testing, but calling it a last resort significantly understates its current role.