Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown
Published: April 11, 2025
Language: Английский
Nature, Journal Year: 2024, Volume and Issue: 629(8011), P. 426 - 434
Published: April 24, 2024
Abstract Expansion of antigen-experienced CD8 + T cells is critical for the success tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer 1 . Interleukin-2 (IL-2) acts as a key regulator cytotoxic functions by promoting expansion and capability 2,3 Therefore, it essential to comprehend mechanistic barriers IL-2 sensing tumour microenvironment implement strategies reinvigorate responsiveness antitumour responses. Here we report that prostaglandin E2 (PGE 2 ), known negative immune response 4,5 , present at high concentrations tissue from leads impaired human TILs via PGE receptors EP2 EP4. Mechanistically, inhibits downregulating IL-2Rγ c chain, resulting defective assembly IL-2Rβ–IL2Rγ membrane dimers. This results IL-2–mTOR adaptation PGC1α transcriptional repression, causing oxidative stress ferroptotic death tumour-reactive TILs. Inhibition signalling EP4 during TIL ACT resulted increased sensing, leading enhanced proliferation control once were transferred vivo. Our study reveals fundamental features underlie impairment mediated microenvironment. These findings have therapeutic implications immunotherapy therapy, enable development targeted enhance amplify TILs, thereby effector potential.
Language: Английский
Citations
59
Cancer Cell, Journal Year: 2024, Volume and Issue: 42(11), P. 1825 - 1863
Published: Oct. 10, 2024
Language: Английский
Citations
57
Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 4, 2024
Language: Английский
Citations
14
Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: unknown
Published: Oct. 24, 2024
Language: Английский
Citations
9
Nature, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 27, 2024
Abstract The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses 1,2 . Within the microenvironment, CD8 + T undergo full effector differentiation acquire cytotoxic functions in specialized niches 3–7 Although interactions with type 1 conventional dendritic have been implicated this process 3–5,8–10 , underlying cellular players molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role intratumoral cell stimulation. These express Cxcl9 Cxcl10 Il15 but contrast to cells, which cross-present antigens, obtain present peptide–major histocompatibility complex class I complexes from through ‘cross-dressing’. Hyperactivation of MAPK signalling hampers coordinately blunting production interferon (IFN-I) cytokines inducing secretion prostaglandin E 2 (PGE ), impairs monocyte state Enhancing IFN-I cytokine blocking PGE restores re-sensitizes tumours cell-mediated immunity. Together, our work uncovers central stimulation, elucidates how oncogenic disrupts counter-regulation IFN-I, proposes rational combination therapies enhance immunotherapies.
Language: Английский
Citations
9
Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)
Published: Jan. 25, 2025
Abstract Cancer development is associated with adaptation to various stressful conditions, such as extracellular acidosis. The adverse tumor microenvironment also selects for increased malignancy. Mitochondria are integral in stress sensing allow cells adapt conditions. Here, we show that colorectal cancer adapted acidic (CRC-AA) more reliant on oxidative phosphorylation than their parental cells, and the acetyl-CoA CRC-AA generated from fatty acids glutamine, but not glucose. Consistently, exhibit mitochondrial mass fitness depends an upregulated autophagic flux-lipid droplet axis. Lipid droplets (LDs) function a buffering system store derived autophagy protect mitochondria lipotoxicity cells. Blockade of LD biogenesis causes dysfunction can be rescued by inhibiting carnitine palmitoyltransferase 1 α (CPT1α). High level superoxide essential AMPK activation, resistance apoptosis, high flux Thus, our results demonstrate cascade formation plays role sustaining promote cell survival under chronic Our findings provide insight into pro-survival metabolic plasticity microenvironmental or therapeutic imply this may potentially targeted therapy.
Language: Английский
Citations
1
Nature Cancer, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 17, 2025
Language: Английский
Citations
1
Cancer Letters, Journal Year: 2024, Volume and Issue: 601, P. 217155 - 217155
Published: Aug. 8, 2024
Immunotherapy has shown promising therapeutic effects in hematological malignancies and certain solid tumors emerged as a critical highly potential treatment modality for cancer. However, prostate cancer falls under the category of immune-resistant cold tumors, which immunotherapy exhibits limited efficacy patients with tumors. Thus, it is important to gain deeper understanding tumor microenvironment facilitate immune system activation overcome suppression advance In this review, we discuss immunosuppressive cancer, characterized by presence few tumor-infiltrating lymphocytes, abundant cells, low immunogenicity, noninflammatory phenotype, significantly influences mainly achieved activating host overcoming immunosuppression. regard, summarize advances checkpoint blockade, immunogenic cell death, reversal microenvironment, vaccines, adjuvants, chimeric antigen receptor T-cell therapy, penetration barriers aim providing novel research insights approaches enhance effectiveness
Language: Английский
Citations
5
Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(11), P. 1215 - 1230
Published: Oct. 14, 2024
Dysregulation of lipid metabolism is a key characteristic the tumor microenvironment, where cells utilize lipids for proliferation, survival, metastasis, and evasion immune surveillance. Lipid has become critical regulator CD8+ T-cell-mediated antitumor immunity, with excess in microenvironment impeding T-cell activities. Considering limited efficacy immunotherapy many solid tumors, targeting to enhance effector functions could significantly improve outcomes. In this review, we examine recent findings on how metabolic processes, including uptake, synthesis, oxidation, regulate T within tumors. We also assessed impact different particular focus affects mitochondrial function tumor-infiltrating cells. Furthermore, as cancer systemic disease, examined factors linking function. Finally, summarize current therapeutic approaches that target increase immunity immunotherapy. Understanding molecular functional interplay between offers promising opportunities treatment.
Language: Английский
Citations
5
Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(11), P. 4717 - 4737
Published: July 27, 2024
Over the past decade, research has increasingly identified unique dysregulations in lipid metabolism within tumor microenvironment (TME). Lipids, diverse biomolecules, not only constitute biological membranes but also function as signaling molecules and energy sources. Enhanced synthesis or uptake of lipids TME significantly promotes tumorigenesis proliferation. Moreover, secreted into influence tumor-resident immune cells (TRICs), thereby aiding survival against chemotherapy immunotherapy. This review aims to highlight recent advancements understanding both TRICs, with a particular emphasis on exogenous endogenous
Language: Английский
Citations
4