TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer?

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13 Citations (Scopus)


Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.
Original languageEnglish
Article number8691
Number of pages17
JournalInternational Journal of Molecular Sciences
Issue number16
Publication statusPublished - 2 Aug 2021

Bibliographical note

Funding Information:
Funding: K.D.R. and C. Goyvaerts were supported by Kom op tegen Kanker, Fonds Wetenschappelijk Onderzoek (FWO) Vlaanderen, Wetenschappelijk Fonds Willy Gepts, and the BCLAS Fund in honor of Jean René Maisin.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Copyright 2022 Elsevier B.V., All rights reserved.


  • lung cancer
  • Immunotherapy
  • immune
  • TNFR1
  • TNFR2


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