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Laubach et al. Cancer Drug Resist 2023;6:611-41 Cancer
DOI: 10.20517/cdr.2023.60
Drug Resistance

Review Open Access

Tumor-intrinsic metabolic reprogramming and how it
drives resistance to anti-PD-1/PD-L1 treatment

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1,2
2
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Kyra Laubach , Tolga Turan , Rebecca Mathew , Julie Wilsbacher , John Engelhardt , Josue Samayoa 1
1
Computational Oncology, AbbVie, South San Francisco, CA 94080, USA.
2
Immuno-Oncology, AbbVie, South San Francisco, CA 94080, USA.
3
Immuno-Oncology, AbbVie, Lake County, IL 60064, USA.
Correspondence to: Dr. Josue Samayoa, Computational Oncology, AbbVie, 1000 Gateway Blvd, South San Francisco, CA
94080, USA. E-mail: josue.samayoa@abbvie.com; Dr. John Engelhardt, Immuno-Oncology, AbbVie, 1000 Gateway Blvd, South
San Francisco, CA 94080, USA. E-mail: john.engelhardt@abbvie.com
How to cite this article: Laubach K, Turan T, Mathew R, Wilsbacher J, Engelhardt J, Samayoa J. Tumor-intrinsic metabolic
reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment. Cancer Drug Resist 2023;6:611-41. https://dx.doi.org/
10.20517/cdr.2023.60
Received: 13 Jun 2023 First Decision: 11 Jul 2023 Revised: 15 Aug 2023 Accepted: 29 Aug 2023 Published: 4 Sep 2023
Academic Editors: Michael Lahn, Godefridus J. Peters Copy Editor: Dong-Li Li Production Editor: Dong-Li Li

Abstract
The development of immune checkpoint blockade (ICB) therapies has been instrumental in advancing the field of
immunotherapy. Despite the prominence of these treatments, many patients exhibit primary or acquired
resistance, rendering them ineffective. For example, anti-programmed cell death protein 1 (anti-PD-1)/anti-
programmed cell death ligand 1 (anti-PD-L1) treatments are widely utilized across a range of cancer indications,
but the response rate is only 10%-30%. As such, it is necessary for researchers to identify targets and develop
drugs that can be used in combination with existing ICB therapies to overcome resistance. The intersection of
cancer, metabolism, and the immune system has gained considerable traction in recent years as a way to
comprehensively study the mechanisms that drive oncogenesis, immune evasion, and immunotherapy
resistance. As a result, new research is continuously emerging in support of targeting metabolic pathways as an
adjuvant to ICB to boost patient response and overcome resistance. Due to the plethora of studies in recent years
highlighting this notion, this review will integrate the relevant articles that demonstrate how tumor-derived
alterations in energy, amino acid, and lipid metabolism dysregulate anti-tumor immune responses and drive
resistance to anti-PD-1/PD-L1 therapy.

Keywords: Immunotherapy resistance, tumor-immune microenvironment, immune checkpoint blockade, energy
metabolism, amino acid metabolism, lipid metabolism

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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