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Navigating metabolic pathways to enhance antitumour immunity and immunotherapy


The development of immunotherapies over the past decade has resulted in a paradigm shift in the treatment of cancer. However, the majority of patients do not benefit from immunotherapy, presumably owing to insufficient reprogramming of the immunosuppressive tumour microenvironment (TME) and thus limited reinvigoration of antitumour immunity. Various metabolic machineries and nutrient-sensing mechanisms orchestrate the behaviour of immune cells in response to nutrient availability in the TME. Notably, tumour-infiltrating immune cells typically experience metabolic stress as a result of the dysregulated metabolic activity of tumour cells, leading to impaired antitumour immune responses. Moreover, the immune checkpoints that are often exploited by tumour cells to evade immunosurveillance have emerging roles in modulating the metabolic and functional activity of T cells. Thus, repurposing of drugs targeting cancer metabolism might synergistically enhance immunotherapy via metabolic reprogramming of the TME. In addition, interventions targeting the metabolic circuits that impede antitumour immunity have been developed, with several clinical trials underway. Herein, we discuss how these metabolic circuits regulate antitumour immunity and the possible approaches to targeting these pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments that could be used to better unleash the potential of adoptive cell therapies by enhancing T cell metabolism.

Key points

  • Conditions in the tumour microenvironment (TME) can impose metabolic stress on infiltrating immune cells, which can result in local immunosuppression and tumour immune evasion.

  • Immune checkpoints mediated by either co-activatory or inhibitory receptors modulate T cell activation and function, in part, by influencing metabolic reprogramming and mitochondrial fitness in these cells.

  • Agents targeting the interacting and competing metabolic pathways that are active in the TME might synergize with immune-checkpoint inhibitors by alleviating metabolic stress in tumour-infiltrating lymphocytes (TILs).

  • Thus, interventions targeting aberrant metabolic properties of tumour cells might reprogramme the immune state of the TME, in particular, via direct and indirect effects on myeloid cells.

  • Modulation of the metabolic programme of T cells during ex vivo TIL expansion or the manufacturing of chimeric antigen receptor (CAR) T cells is a promising strategy to improve efficacy of adoptive T cell-based immunotherapies.

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The work of P.R. is supported in part by the Swiss National Science Foundation (CRSII3_160708 and 31003A_156469 grants) and a research grant from Roche Pharma Research and Early Development (pRED). The work of S.C.-C.H. is supported by a Case Comprehensive Cancer Center ASC Pilot Award (IRG-91-022-19). S.-M.F. acknowledges research funding from the European Research Council (ERC) (ERC Consolidator Grant agreement number 771486 — MetaRegulation), the Research Foundation — Flanders (FWO; Odysseus Group II, Research Grants and Research Projects) and KU Leuven (Methuselah Co-Funding). The work of P.-C.H. is supported in part by the Swiss National Science Foundation (31003A_163204 and 31003A_182470 grants), the Melanoma Research Alliance, the Cancer Research Institute (CLIP award), Roche pRED and the Swiss Cancer League (grant KFS-3949-08-2016).

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All authors made substantial contributions to researching the data, discussions of content and writing of the manuscript and reviewed and edited the manuscript.

Competing interests

P.R. is a member of the scientific advisory board of Immatics and NexImmune and has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb and Roche and research funding from Roche in the form of a Pharma Research and Early Development (pRED) grant. S.-M.F. has received funding from Bayer and Merck. P.-C.H. has received research funding from Idorsia, Novartis and Roche (pRED grant) and speaker honoraria from Chugai and Pfizer and is a member of the scientific advisory board of Elixiron Immunotherapeutics. The other authors declare no competing interests.

Correspondence to Ping-Chih Ho.

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Fig. 1: Metabolic stress in the tumour microenvironment and its impact on antitumour immunity.
Fig. 2: Modulation of metabolic pathways by immune-checkpoint receptors and ligands.
Fig. 3: Metabolic approaches to enhancing adoptive T cell therapy.