Obesity induces PD-1 on macrophages to suppress anti-tumour immunity

Nature. 2024 Jun;630(8018):968-975. doi: 10.1038/s41586-024-07529-3. Epub 2024 Jun 12.


Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.

MeSH terms

  • Animals
  • Antigen Presentation / drug effects
  • B7-2 Antigen / antagonists & inhibitors
  • B7-2 Antigen / immunology
  • B7-2 Antigen / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Female
  • Glycolysis / drug effects
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Lymphocyte Activation
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms* / drug therapy
  • Neoplasms* / immunology
  • Neoplasms* / metabolism
  • Neoplasms* / pathology
  • Obesity* / immunology
  • Obesity* / metabolism
  • Phagocytosis / drug effects
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / metabolism
  • Tumor-Associated Macrophages* / drug effects
  • Tumor-Associated Macrophages* / immunology
  • Tumor-Associated Macrophages* / metabolism


  • B7-2 Antigen
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Immune Checkpoint Inhibitors
  • Inflammation Mediators
  • Mechanistic Target of Rapamycin Complex 1
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor