Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. Trained immunity: A program of innate immune memory in health and disease. Science. 2016;352:aaf1098.
Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, et al. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol. 2021;22:2–6.
Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20:375–88.
Cheng S-C, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684.
Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345:1251086.
Mulder WJM, Ochando J, Joosten LAB, Fayad ZA, Netea MG. Therapeutic targeting of trained immunity. Nat Rev Drug Discov. 2019;18:553–66.
Wang T, Wang Y, Zhang J, Yao Y. Role of trained innate immunity against mucosal cancer. Curr Opin Virol. 2024;64:101387.
van Puffelen JH, Keating ST, Oosterwijk E, van der Heijden AG, Netea MG, Joosten L, et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nat Rev Urol. 2020;17:513–25.
Ding C, Shrestha R, Zhu X, Geller AE, Wu S, Woeste MR, et al. Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis. Nat Immunol. 2023;24:239–54.
Priem B, van Leent M, Teunissen A, Sofias AM, Mourits VP, Willemsen L, et al. Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition. Cell. 2020;183:786–801.e19.
Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M, Damjanovic D, et al. Induction of Autonomous Memory Alveolar Macrophages Requires T-Cell Help and Is Critical to Trained Immunity. Cell. 2018;175:1634–50.e17.
Wang T, Zhang J, Wang Y, Li Y, Wang L, Yu Y, et al. Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs. Nat Immunol. 2023;24:423–38.
Arts R, Moorlag S, Novakovic B, Li Y, Wang SY, Oosting M, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018;23:89–100.e5.
Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S, Antonakos N, Kotsaki A, Domínguez-Andrés J, et al. Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly. Cell. 2020;183:315–23.e9.
Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE, Pacis A, et al. BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell. 2018;172:176–90.e19.
Jeyanathan M, Vaseghi-Shanjani M, Afkhami S, Grondin JA, Kang A, D’Agostino MR, et al. Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut–lung axis. Nat Immunol. 2022;23:1687–702.
Mata-Martínez P, Bergón-Gutiérrez M, Del Fresno C. Dectin-1 Signaling Update: New Perspectives for Trained Immunity. Front Immunol. 2022;13:812148.
Khan N, Downey J, Sanz J, Kaufmann E, Blankenhaus B, Pacis A, et al. M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity. Cell. 2020;183:752–70.e22.
Murphy J, Summer R, Wilson AA, Kotton DN, Fine A. The prolonged life-span of alveolar macrophages. Am J Respir Cell Mol Biol. 2008;38:380–5.
Aegerter H, Lambrecht BN, Jakubzick CV. Biology of lung macrophages in health and disease. Immunity. 2022;55:1564–80.
Kopf M, Schneider C, Nobs SP. The development and function of lung-resident macrophages and dendritic cells. Nat Immunol. 2015;16:36–44.
Eguíluz-Gracia I, Schultz HH, Sikkeland LI, Danilova E, Holm AM, Pronk CJ, et al. Long-term persistence of human donor alveolar macrophages in lung transplant recipients. Thorax. 2016;71:1006–11.
Zahalka S, Starkl P, Watzenboeck ML, Farhat A, Radhouani M, Deckert F, et al. Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling. Mucosal Immunol. 2022;15:896–907.
Leopold Wager CM, Hole CR, Campuzano A, Castro-Lopez N, Cai H, Caballero Van Dyke MC, et al. IFN-gamma immune priming of macrophages in vivo induces prolonged STAT1 binding and protection against Cryptococcus neoformans. PLoS Pathog. 2018;14:e1007358.
Lazear HM, Schoggins JW, Diamond MS. Shared and Distinct Functions of Type I and Type III Interferons. Immunity. 2019;50:907–23.
Connolly E, Hussell T. The Impact of Type 1 Interferons on Alveolar Macrophage Tolerance and Implications for Host Susceptibility to Secondary Bacterial Pneumonia. Front Immunol. 2020;11:495.
Kamada R, Yang W, Zhang Y, Patel MC, Yang Y, Ouda R, et al. Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc Natl Acad Sci USA. 2018;115:E9162–71.
Aegerter H, Kulikauskaite J, Crotta S, Patel H, Kelly G, Hessel EM, et al. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat Immunol. 2020;21:145–57.
Li, F, Piattini F, Pohlmeier L, Feng Q, Rehrauer H, Kopf M. Monocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection. Sci Immunol. 2022;7:eabj5761.
Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014;159:1312–26.
Gibbings SL, Goyal R, Desch AN, Leach SM, Prabagar M, Atif SM, et al. Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood. 2015;126:1357–66.
Lercher A, Cheong JG, Bale MJ, Jiang C, Hoffmann HH, Ashbrook AW, et al. Antiviral innate immune memory in alveolar macrophages after SARS-CoV-2 infection ameliorates secondary disease caused by influenza A virus. Immunity. 2024;57:2530-2546.e13.
Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91.
Zhang J, Wang T, Wang Y, Li Y, Wang L, Wang J, et al. Bacterial pneumonia induces senescence in resident alveolar macrophages that are outcompeted by monocytes. Cell Rep. 2025;44:115571.
Mizutani T, Neugebauer N, Putz EM, Moritz N, Simma O, Zebedin-Brandl E, et al. Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance. Oncoimmunology. 2012;1:1027–37.
Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 2018;18:545–58.
Novakovic B, Habibi E, Wang SY, Arts R, Davar R, Megchelenbrink W, et al. β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance. Cell. 2016;167:1354–68.e14.
Mould KJ, Moore CM, McManus SA, McCubbrey AL, McClendon JD, Griesmer CL, et al. Airspace macrophages and monocytes exist in transcriptionally distinct subsets in healthy adults. Am J Respir Crit Care Med. 2021;203:946–56.
Leader AM, Grout JA, Maier BB, Nabet BY, Park MD, Tabachnikova A, et al. Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification. Cancer Cell. 2021;39:1594–609.e12.
Singh AK, Praharaj M, Lombardo KA, Yoshida T, Matoso A, Baras AS, et al. Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer. Nat Commun. 2022;13:878.
Netea MG, Giamarellos-Bourboulis EJ, Domínguez-Andrés J, Curtis N, van Crevel R, van de Veerdonk FL, et al. Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection. Cell. 2020;181:969–77.
Joseph J. Trained Immunity as a Prospective Tool against Emerging Respiratory Pathogens. Vaccines (Basel). 2022;10:1932.
Netea MG, Joosten LAB, van der Meer JWM. Hypothesis: stimulation of trained immunity as adjunctive immunotherapy in cancer. J Leukoc Biol. 2017;102:1323–32.
Lérias JR, de Sousa E, Paraschoudi G, Martins J, Condeço C, Figueiredo N, et al. Trained Immunity for Personalized Cancer Immunotherapy: Current Knowledge and Future Opportunities. Front Microbiol. 2019;10:2924.
Geller AE, Shrestha R, Woeste MR, Guo H, Hu X, Ding C, et al. The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression. Nat Commun. 2022;13:759.
Van Puffelen, JH, Novakovic B, van Emst L, Kooper D, Zuiverloon T, Oldenhof U, et al. Intravesical BCG in patients with nonmuscle invasive bladder cancer induces trained immunity and decreases respiratory infections. J Immunother Cancer. 2023;11:e005518.
Kalafati L, Kourtzelis I, Schulte-Schrepping J, Li X, Hatzioannou A, Grinenko T, et al. Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity. Cell. 2020;183:771–785.e12.
Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015;15:405–14.
Holicek P, Guilbaud E, Klapp V, Truxova I, Spisek R, Galluzzi L, et al. Type I interferon and cancer. Immunol Rev. 2024;321:115–27.
Swiecki M, Colonna M. Type I interferons: diversity of sources, production pathways and effects on immune responses. Curr Opin Virol. 2011;1:463–75.
Chin EN, Sulpizio A, Lairson, LL. Targeting STING to promote antitumor immunity. Trends Cell Biol. 2023;33:189–203.
Schliehe C, Flynn EK, Vilagos B, Richson U, Swaminanthan S, Bosnjak B, et al. The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection. Nat Immunol. 2015;16:67–74.
Sun L, Kees T, Almeida AS, Liu B, He XY, Ng D, et al. Activating a collaborative innate-adaptive immune response to control metastasis. Cancer Cell. 2021;39:1361–74.e9.
Careau E, Bissonnette EY. Adoptive transfer of alveolar macrophages abrogates bronchial hyperresponsiveness. Am J Respir Cell Mol Biol. 2004;31:22–7.
Suzuki T, Arumugam P, Sakagami T, Lachmann N, Chalk C, Sallese A, et al. Pulmonary macrophage transplantation therapy. Nature. 2014;514:450–4.
Casanova-Acebes M, Dalla E, Leader AM, LeBerichel J, Nikolic J, Morales BM, et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature. 2021;595:578–84.
Sharma SK, Chintala NK, Vadrevu SK, Patel J, Karbowniczek M, Markiewski MM. Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T-cell responses in the lungs. J Immunol. 2015;194:5529–38.
Subramanian S, Busch CJ, Molawi K, Geirsdottir L, Maurizio J, Vargas Aguilar S, et al. Long-term culture-expanded alveolar macrophages restore their full epigenetic identity after transfer in vivo. Nat Immunol. 2022;23:458–68.
Hao Y, Stuart T, Kowalski MH, Choudhary S, Hoffman P, Hartman A, et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat Biotechnol. 2024;42:293–304.