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  • Review Article
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Reconsidering adjuvant and perioperative immune-checkpoint inhibition: de-escalation, expansion and personalization

Nature Reviews Clinical Oncology (2026)Cite this article

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Abstract

Anti-PD-L1 antibodies have transformed cancer treatment and are increasingly being used in patients with early-stage malignancies including in the adjuvant and neoadjuvant settings. In certain cancers, earlier administration of these agents reduces the risk of metastatic disease and might improve overall survival. Thus far, however, overall survival benefits in the adjuvant setting have yet to be clearly demonstrated in all tumour types probably owing to a lack of long-term follow-up and/or the confounding effects of anti-PD-L1 antibody monotherapy and/or combinations in the metastatic setting, in which these agents can also produce durable responses. In this Review, we explore the optimal use of anti-PD-L1 antibodies in the adjuvant and perioperative settings, using examples from melanoma, renal cell carcinoma and non-small-cell lung cancer. We examine de-escalation strategies, including shortening treatment duration or deferring therapy to time of recurrence, at which point anti-PD-L1 antibodies might be more likely to be administered in combination; the expansion of certain specific indications, potentially leading to more effective combinations and/or use in biomarker-defined patients with high-risk early-stage disease; and selecting the most appropriate indication, with emerging data suggesting that neoadjuvant or perioperative use of anti-PD-L1 antibodies might be more effective than adjuvant use in certain cancers, as well as the possibility of personalization of therapy guided by biomarkers such as circulating tumour DNA or other emerging assays.

Key points

  • Adjuvant therapy with an immune-checkpoint inhibitor (ICI) has become a standard option for patients with many high-risk, resected solid tumours.

  • Neoadjuvant or perioperative ICIs improve outcomes compared with adjuvant therapy in patients with melanoma and probably also in those with other cancers and are increasingly being used.

  • The efficacy of ICI monotherapy and combination therapy in the metastatic setting raises the question as to whether adjuvant therapy should be used or deferred, particularly for patients with a lower risk of disease recurrence.

  • Both circulating tumour DNA and pathological complete responses are promising biomarkers that are likely to help attempts to personalize the use of adjuvant ICIs.

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Fig. 1: Rationale and clinical considerations for the optimal timing of immune-checkpoint inhibitor administration.
Fig. 2: Clinical framework for investigations, considerations and treatment decisions relating to adjuvant therapy with immune-checkpoint inhibitors.

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Author notes

  1. These authors contributed equally: Douglas B. Johnson, Abdul Rafeh Naqash, Ryan J. Sullivan.

Authors and Affiliations

  1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Douglas B. Johnson, Mehmet Murat Zerey & Brian I. Rini

  2. Department of Medicine, Yale University Medical Center, New Haven, CT, USA

    Amin H. Nassar

  3. Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA

    Ayesha Aijaz & Abdul Rafeh Naqash

  4. Mass General Brigham Cancer Institute, Harvard Medical School, Boston, MA, USA

    Andrew Knight & Ryan J. Sullivan

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Contributions

D.B.J., A.K. and A.R.N. researched data for the manuscript. All authors made a substantial contribution to discussions of content, wrote the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to Douglas B. Johnson.

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Competing interests

D.B.J. has acted as a consultant and/or adviser of AstraZeneca, BMS, Daiichi Sankyo, ImmunoEngineering, Merck, Mosaic, Novartis, Pfizer, Teiko, The Jackson Laboratory and Therakos, has received research funding from BMS and Incyte and has patents pending relating to the use of MHC-II as a biomarker for response to immune-checkpoint inhibitors and abatacept for immune-related adverse events. A.H.N. has acted as a consultant of Capvision, Guidepoint Global and Putnam Associates, has received honoraria from the Korean Society of Medical Oncology, Oklahoma University, OncLive, Targeted Oncology and TEMPUS, has received travel support from the American Association for Cancer Research and the Korean Society of Medical Oncology, has received compensation from Outlier.ai for providing feedback on data analysis tools and AI development and holds equity in Revolution Medicine and Summit Therapeutics. B.I.R. has acted as a consultant of AstraZeneca, Aveo, BMS, Deciphera, Eisai, Merck, Pfizer and Xencor and has received research funding from AstraZeneca, Arcus, Aveo, BMS, Merck, Pfizer and Roche. A.R.N. has acted as a consultant and/or adviser of Astellas and Foundation Medicine, has received travel support from Jazz Pharmaceuticals and honoraria from NGM Biopharmaceuticals. R.J.S. has acted as a consultant and/or adviser of Marengo, Merck, Novartis, Pfizer and Replimune, has received research funding from Merck and royalties/licenses from UpToDate. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks G. Mountzios, who co-reviewed with K. Papavassiliou, and M. Postow for their contribution to the peer review of this work.

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Johnson, D.B., Nassar, A.H., Aijaz, A. et al. Reconsidering adjuvant and perioperative immune-checkpoint inhibition: de-escalation, expansion and personalization. Nat Rev Clin Oncol (2026). https://doi.org/10.1038/s41571-026-01123-4

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