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    Immune checkpoint inhibitors

    Also known as checkpoint inhibitors, checkpoint blockade, PD-1 inhibitors, ICIs

    Immune checkpoint inhibitors are antibodies that block brake proteins such as PD-1, PD-L1 and CTLA-4 so T cells can attack cancer.[1][2] The first was approved in 2011, and they remain the backbone of cancer immunotherapy, though only a minority of patients respond.[3][4]

    Editor reviewedStrict sourcingUpdated Cancer immunotherapyHealth and medicineLife sciences
    Key facts

    Immune checkpoint inhibitors are antibody drugs that block the immune system’s natural brakes so that T cells can attack tumours.[1] They were the first immunotherapies to work across many cancer types and are the backbone that newer approaches are combined with or measured against.[3][5]

    How they work

    Immune checkpoints normally stop immune responses from becoming so strong that they damage healthy cells.[6] Some tumours exploit this by producing large amounts of PD-L1, which turns down T-cell responses; blocking the binding restores them.[1] The two main pathways act in different places: CTLA-4 mainly during T-cell activation in lymph nodes, PD-1 mainly in tissues where its ligands are expressed in the tumour microenvironment.[2]

    History and scale

    The FDA approved the first checkpoint inhibitor, the CTLA-4 antibody ipilimumab, in 2011 for advanced melanoma.[3] The science behind the class won the 2018 Nobel Prize in Physiology or Medicine, awarded to James P. Allison, who studied CTLA-4, and Tasuku Honjo, who discovered PD-1, for showing how releasing these brakes could treat cancer.[7] Merck’s PD-1 antibody pembrolizumab (Keytruda) recorded $31.7 billion in sales in 2025, including a subcutaneous version, Keytruda Qlex.[8] The FDA approved Keytruda Qlex on 19 September 2025 for the solid-tumour uses of the intravenous drug, in adults and children 12 and older.[9] In the 377-patient lung cancer trial behind it, response rates were 45% for the injection and 42% for the infusion, with no notable difference in survival.[9][10]

    Who benefits

    Eligibility has grown much faster than benefit. A 2019 study estimated that 43.6% of US patients with cancer were eligible for a checkpoint inhibitor in 2018, but only about 12.5% would respond.[4] Approvals keep moving checkpoint inhibitors into earlier disease. In October 2026 the FDA approved atezolizumab with chemotherapy after surgery for stage III mismatch repair deficient colon cancer, where the ATOMIC trial showed a disease-free survival hazard ratio of 0.50.[11] Earlier in 2026 the FDA approved nivolumab with chemotherapy for untreated Hodgkin lymphoma and durvalumab with BCG for high-risk non-muscle invasive bladder cancer.[12]

    Timing matters as well as target. In the phase 3 NADINA trial, 423 patients with resectable stage III melanoma received either two cycles of ipilimumab plus nivolumab before surgery or surgery followed by a year of nivolumab. Twelve-month event-free survival was 83.7% with the neoadjuvant approach versus 57.2% (hazard ratio 0.32).[13] The trade-off was more serious side effects: grade 3 or higher treatment-related events occurred in 29.7% versus 14.7%.[14]

    Side effects

    Because checkpoints protect healthy tissue, side effects are immune-mediated. Rash, diarrhoea and fatigue are common, and rarer effects include inflammation of organs such as the lungs, colon, liver, heart and thyroid.[15] In one ipilimumab melanoma trial, 64% of patients had an immune-related adverse event and 18% had one of grade 3 or higher.[16]

    Where the field is going

    Much current work pairs checkpoint inhibitors with other agents. A personalised mRNA vaccine plus pembrolizumab beat pembrolizumab alone in a phase 3 melanoma trial announced in August 2026.[5] The ADC sacituzumab govitecan plus pembrolizumab was approved for first-line PD-L1-positive triple-negative breast cancer in June 2026.[17] An earlier ADC pairing, enfortumab vedotin plus pembrolizumab, nearly doubled median overall survival against platinum chemotherapy in untreated advanced bladder cancer in the EV-302 trial (31.5 vs 16.1 months).[18] A new class of bispecific antibodies fuses PD-1 blockade with VEGF inhibition: ivonescimab beat pembrolizumab on overall survival in the HARMONi-2 lung cancer trial, according to its developer Akeso.[19] See bispecific-t-cell-engagers and personalized-neoantigen-vaccines.

    Questions readers ask

    How do checkpoint inhibitors work?

    Some tumours turn down T-cell responses by producing large amounts of PD-L1. Checkpoint inhibitors block the binding between checkpoint proteins so T cells can attack the cancer.[1]

    What was the first checkpoint inhibitor?

    Ipilimumab (Yervoy), which blocks CTLA-4, approved by the FDA in 2011 for advanced melanoma.[3]

    How many patients benefit?

    A 2019 study estimated that in 2018 about 43.6% of US cancer patients were eligible for checkpoint inhibitors and about 12.5% would respond.[4]

    What side effects do they cause?

    Common effects include rash, diarrhoea and fatigue. Rarer effects include widespread inflammation that can affect organs such as the lungs, colon, liver, heart and thyroid.[15]

    Can checkpoint inhibitors be given before surgery?

    Yes, in some cancers. In the NADINA trial in stage III melanoma, two doses of ipilimumab plus nivolumab before surgery gave 83.7% 12-month event-free survival versus 57.2% with surgery followed by nivolumab.[13]

    Is there an injection instead of an infusion?

    Yes. In September 2025 the FDA approved Keytruda Qlex, a subcutaneous form of pembrolizumab, for its solid-tumour indications.[9]

    Sources

    Each numbered claim is a statement we checked against the sources listed with it. Status shows how well established it is.

    1. [1]

      Some tumours dampen T-cell responses by producing large amounts of the checkpoint protein PD-L1; checkpoint inhibitors block this binding so T cells can attack the cancer. confirmedas of 2026-10-10

    2. [2]

      The CTLA-4 pathway acts mainly at the level of lymph nodes during initial T-cell activation, while the PD-1 pathway acts mainly in tissues, where its ligands PD-L1 and PD-L2 are expressed in the tumour microenvironment. confirmedas of 2026-10-10

    3. [3]

      Ipilimumab (Yervoy), which blocks CTLA-4, became the first immune checkpoint inhibitor approved by the FDA, in 2011, for unresectable or metastatic melanoma. confirmedas of 2026-10-10

    4. [4]

      A 2019 study estimated that 43.6% of US patients with cancer were eligible for checkpoint inhibitors in 2018 but only about 12.5% would respond to them. confirmedas of 2019-05-03

    5. [5]

      Merck and Moderna announced on 19 August 2026 that the 1,137-patient phase 3 INTerpath-001 trial of intismeran autogene plus Keytruda in resected stage IIB-IV melanoma met its primary endpoint of recurrence-free survival and key secondary endpoint of distant metastasis-free survival versus Keytruda alone. confirmedas of 2026-08-19

    6. [6]

      Immune checkpoints are a normal part of the immune system that stop immune responses from becoming so strong that they destroy healthy cells. confirmedas of 2026-10-10

    7. [7]

      The 2018 Nobel Prize in Physiology or Medicine was awarded jointly to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation, the basis of CTLA-4 and PD-1 checkpoint blockade. confirmedas of 2018-10-01

    8. [8]

      Merck reported 2025 worldwide sales of $31.7 billion for its PD-1 inhibitor Keytruda (pembrolizumab), including the subcutaneous Keytruda Qlex. confirmedas of 2026-02-03

    9. [9]

      On 19 September 2025 the FDA approved Keytruda Qlex, pembrolizumab with berahyaluronidase alfa for subcutaneous injection, for the solid-tumour indications of intravenous pembrolizumab in adults and children 12 and older, based on a 377-patient lung cancer trial showing comparable drug exposure. confirmedas of 2025-09-19

    10. [10]

      In the trial supporting Keytruda Qlex, the confirmed overall response rate was 45% with subcutaneous pembrolizumab and 42% with the intravenous form, with no notable differences in progression-free or overall survival. confirmedas of 2025-09-19

    11. [11]

      On 8 October 2026 the FDA approved atezolizumab plus chemotherapy as adjuvant treatment for stage III mismatch repair deficient colon cancer, based on the ATOMIC trial (disease-free survival hazard ratio 0.50). confirmedas of 2026-10-08

    12. [12]

      FDA checkpoint-inhibitor approvals in 2026 included nivolumab with chemotherapy for untreated Hodgkin lymphoma (20 March) and durvalumab with BCG for high-risk non-muscle invasive bladder cancer (28 May). confirmedas of 2026-10-10

    13. [13]

      In the phase 3 NADINA trial of 423 patients with resectable stage III melanoma, two cycles of neoadjuvant ipilimumab plus nivolumab before surgery gave 12-month event-free survival of 83.7% versus 57.2% with surgery followed by adjuvant nivolumab (hazard ratio 0.32). confirmedas of 2024-06-02

    14. [14]

      In NADINA, 59.0% of neoadjuvant patients had a major pathological response, and grade 3 or higher treatment-related adverse events occurred in 29.7% of the neoadjuvant group versus 14.7% of the adjuvant group. confirmedas of 2024-06-02

    15. [15]

      Common side effects of checkpoint inhibitors include rash, diarrhoea and fatigue; rarer effects include widespread inflammation that can affect organs such as the lungs, colon, liver, heart and thyroid. confirmedas of 2026-10-10

    16. [16]

      In an ipilimumab melanoma trial, 64% of patients had an immune-related adverse event of any grade and 18% had one of grade 3 or higher. confirmedas of 2026-10-10

    17. [17]

      On 24 June 2026 the FDA approved the Trop-2-directed ADC sacituzumab govitecan with pembrolizumab for first-line PD-L1-positive metastatic triple-negative breast cancer; median progression-free survival was 11.2 versus 7.8 months in ASCENT-04. confirmedas of 2026-06-24

    18. [18]

      In the phase 3 EV-302 trial of 886 patients with previously untreated advanced urothelial cancer, enfortumab vedotin plus pembrolizumab roughly doubled median overall survival versus platinum chemotherapy (31.5 vs 16.1 months; hazard ratio 0.47) and progression-free survival (12.5 vs 6.3 months). confirmedas of 2024-03-01

    19. [19]

      Akeso reported in September 2026 that its PD-1 x VEGF bispecific ivonescimab extended median overall survival to 30.8 months versus 22.6 months with pembrolizumab in first-line PD-L1-positive non-small cell lung cancer in the HARMONi-2 trial (hazard ratio 0.73). confirmedas of 2026-09-13

    Revision history (2)
    1. Page created.
    2. Refresh: added the 2018 Nobel Prize, Keytruda Qlex approval details, NADINA neoadjuvant melanoma results and EV-302.

    Created Oct 10, 2026. Last reviewed by an editor on Oct 10, 2026. Next scheduled review: Jan 10, 2027.

    Cite this page

    "Immune checkpoint inhibitors." ContentLora, updated Oct 10, 2026. https://contentlora.com/wiki/immune-checkpoint-inhibitors

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