Lim, S. A., Su, W., Chapman, N. M. & Chi, H. Lipid metabolism in T cell signaling and function. Nat. Chem. Biol. 18, 470â481 (2022).
Zhang, Y. et al. Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32, 377â391.e9 (2017).
Nava Lauson, C. B. et al. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity. Cell Metab. 35, 633â650.e639 (2023).
Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252â256 (2017).
Lin, R. et al. Fatty acid oxidation controls CD8+ tissue-resident memory T-cell survival in gastric adenocarcinoma. Cancer Immunol. Res. 8, 479â492 (2020).
Reinfeld, B. I. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593, 282â288 (2021).
Long, L. et al. CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity. Nature 600, 308â313 (2021).
Fox, C. J., Hammerman, P. S. & Thompson, C. B. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5, 844â852 (2005).
Byersdorfer, C. A. et al. Effector T cells require fatty acid metabolism during murine graft-versus-host disease. Blood 122, 3230â3237 (2013).
Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103â107 (2009).
Jin, R. et al. Role of FABP5 in T cell lipid metabolism and function in the tumor microenvironment. Cancers 15, 657 (2023).
Liu, F. et al. Identification of FABP5 as an immunometabolic marker in human hepatocellular carcinoma. J. Immunother. Cancer 8, e000501 (2020).
Matulonis, U. A. et al. Ovarian cancer. Nat. Rev. Dis. Primers 2, 16061 (2016).
Matulonis, U. A. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann. Oncol. 30, 1080â1087 (2019).
Kandalaft, L. E., Dangaj Laniti, D. & Coukos, G. Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat. Rev. Cancer 22, 640â656 (2022).
Song, M. et al. IRE1αâXBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562, 423â428 (2018).
Cao, Y. et al. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat. Commun. 10, 1280 (2019).
Anadon, C. M. et al. Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells. Cancer Cell 40, 545â557.e13 (2022).
Bowtell, D. D. The genesis and evolution of high-grade serous ovarian cancer. Nat. Rev. Cancer 10, 803â808 (2010).
Digre, A. & Lindskog, C. The Human Protein Atlasâspatial localization of the human proteome in health and disease. Protein Sci. 30, 218â233 (2021).
Conejo-Garcia, J. R. et al. Tumor-infiltrating dendritic cell precursors recruited by a β-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat. Med. 10, 950â958 (2004).
Chae, C. S. et al. Tumor-derived lysophosphatidic acid blunts protective type-I interferon responses in ovarian cancer. Cancer Discov. 12, 1904â1921 (2022).
Cubillos-Ruiz, J. R. et al. Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. Cancer Res. 72, 1683â1693 (2012).
Cubillos-Ruiz, J. R. et al. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J. Clin. Invest. 119, 2231â2244 (2009).
Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527â1538 (2015).
Scarlett, U. K. et al. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J. Exp. Med. 209, 495â506 (2012).
Szklarczyk, D. et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 49, D605âD612 (2021).
Wan, C. H. et al. Panorama of ancient metazoan macromolecular complexes. Nature 525, 339â344 (2015).
Yin, L. M., Ulloa, L. & Yang, Y. Q. Transgelin-2: biochemical and clinical implications in cancer and asthma. Trends Biochem. Sci. 44, 885â896 (2019).
Jo, S., Kim, H. R., Mun, Y. & Jun, C. D. Transgelin-2 in immunity: Its implication in cell therapy. J. Leukoc. Biol. 104, 903â910 (2018).
Ortega, F. J. et al. Cytoskeletal transgelin 2 contributes to gender-dependent adipose tissue expandability and immune function. FASEB J. 33, 9656â9671 (2019).
Na, B. R. et al. TAGLN2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse. J. Cell Biol. 209, 143â162 (2015).
Armstrong, E. H., Goswami, D., Griffin, P. R., Noy, N. & Ortlund, E. A. Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor β/δ (FABP5-PPARβ/δ) signaling pathway. J. Biol. Chem. 289, 14941â14954 (2014).
Furuhashi, M. & Hotamisligil, G. S. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat. Rev. Drug Discovery 7, 489â503 (2008).
Fung, H. Y., Teryek, M., Lemenze, A. D. & Bergsbaken, T. CD103 fate mapping reveals that intestinal CD103â tissue-resident memory T cells are the primary responders to secondary infection. Sci. Immunol. 7, eabl9925 (2022).
Giles, J. R. et al. Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics. Nat. Immunol. 23, 1600â1613 (2022).
Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189â196 (2016).
Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270â274 (2019).
Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421â438 (2020).
Chen, X. & Cubillos-Ruiz, J. R. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat. Rev. Cancer 21, 71â88 (2021).
Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881â891 (2001).
Logue, S. E. et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat. Commun. 9, 3267 (2018).
Morita, S. et al. Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes. Cell Metab. 25, 1207 (2017).
Di Conza, G., Ho, P. C., Cubillos-Ruiz, J. R. & Huang, S. C. Control of immune cell function by the unfolded protein response. Nat. Rev. Immunol. 23, 546â562 (2023).
Kim, H. R. et al. An essential role for TAGLN2 in phagocytosis of lipopolysaccharide-activated macrophages. Sci. Rep. 7, 8731 (2017).
Iyer, S. et al. Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy. Cancer Discov. 11, 384â407 (2021).
Zhang, K. Y. et al. Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer. Sci. Adv. 8, eabm1831 (2022).
Snaebjornsson, M. T., Janaki-Raman, S. & Schulze, A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab. 31, 62â76 (2020).
Shender, V. O. et al. Proteomeâmetabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication. Mol. Cell. Proteomics 13, 3558â3571 (2014).
Perales-Puchalt, A. et al. Follicle-stimulating hormone receptor is expressed by most ovarian cancer subtypes and is a safe and effective immunotherapeutic target. Clin. Cancer Res. 23, 441â453 (2017).
Paffenholz, S. V. et al. Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer. Proc. Natl Acad. Sci. USA 119, e2117754119 (2022).
Pramanik, J. et al. Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation. Genome Med. 10, 76 (2018).
Bogdan, D. M. et al. FABP5 deletion in nociceptors augments endocannabinoid signaling and suppresses TRPV1 sensitization and inflammatory pain. Sci. Rep. 12, 9241 (2022).
Lee, A. H., Scapa, E. F., Cohen, D. E. & Glimcher, L. H. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320, 1492â1496 (2008).
Iwawaki, T., Akai, R., Yamanaka, S. & Kohno, K. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc. Natl Acad. Sci. USA 106, 16657â16662 (2009).
Chopra, S. et al. IRE1뱉XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science 365, eaau6499 (2019).
de Boer, J. et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur. J. Immunol. 33, 314â325 (2003).
Roby, K. F. et al. Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis 21, 585â591 (2000).
Ichikawa, T. et al. Chemical fixation creates nanoscale clusters on the cell surface by aggregating membrane proteins. Commun. Biol. 5, 487 (2022).
Bolte, S. & Cordelieres, F. P. A guided tour into subcellular colocalization analysis in light microscopy. J. Microsc. 224, 213â232 (2006).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573â3587.e29 (2021).
Xu, J. et al. Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer. Clin. Cancer Res. 28, 3590â3602 (2022).
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495â502 (2015).
Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).
Andreatta, M. et al. Interpretation of T cell states from single-cell transcriptomics data using reference atlases. Nat. Commun. 12, 2965 (2021).
Chu, Y. et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat. Med. 29, 1550â1562 (2023).
Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211â218 (2019).
Wu, T. et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).