Our lab studies dendritic cells (DCs) and macrophages, key immune sentinels that regulate immunity, inflammation, and tolerance. As gatekeepers of the immune system, these cells not only defend against pathogens but also maintain balance to prevent self-damage. Because of their unique ability to shape immune responses, they are promising targets for new therapies against infectious, autoimmune, cardiovascular diseases (CVD), and cancer. We also explore the dialogue between the microbiota and the immune system.

The discovery of how microbes activate immune system cells has contributed to a revolution in the field of immunology in the 21st century. However, the recognition of microbial patterns does not explain the immune response in processes that occur in the apparent absence of infection, such as cancer. I received funding from the ERC Starting Grant (December 2010) to investigate how DCs sense danger signals associated to tissue damage, for instance, to tumors damaged with radio or chemotherapy. Our results established that DCs can detect tissue damage signals to regulate cross-presentation through DNGR-1, orchestrating the generation of adaptive CD8+ T cell responses critical for anti-tumor immunity (Iborra et al. J Clin Invest 2012, Blanco-Menéndez et al. J Immunol 2015, Iborra et al. Immunity 2016a, del Fresno et al. Science 2018). We next explored the role of DNGR-1 in the context of cancer. In addition to its role in cross-presentation, we also found that DNGR-1 regulates the infiltration of cDC1s within the tumor, a key factor to boost anti-cancer immunity (Cueto et al. J. Immunother. Cancer. 2021). These results on the important role of DCs (and particularly the cDC1 subset identified by expression of CLEC9A/DNGR-1) on generation of anti-tumor immunity led us to collaborate with clinicians in a European consortium funded by H2020 (2016-2021) to generate preclinical data on the application of cDC1s in anti-tumor immunotherapy. Our research has generated significant advances to better understand how cDC1s work and to seek their clinical application in immunotherapy. An initial work found that cDC1s can selectively generate resident memory T cells, which stay in the tissues (Iborra et al. Immunity 2016b). Next, we found that resident memory T cells have a relevant role in anti-tumor response, in collaboration with circulating memory T cells, being CD103+ resident memory T cells in the human tumors a marker for good prognosis and further demonstrating an important role of cDC1s in restimulation of anti-cancer immunity within the tumor (Enamorado et al. Nat Commun 2017). Next, we questioned the role of cross-presenting DCs in the efficacy of immune checkpoint blockade (ICB) and were first to show that cDC1s are crucial for ICB efficacy (Sánchez-Paulete et al. Cancer Discovery 2016). In our preclinical validation for the consortium we purified and adoptively transferred cDC1s (activated and incubated with tumor lysate to capture tumor antigens) to mice with different tumors and found a high efficacy of cDC1-driven immunotherapy in tumor therapy (Wculek et al. J. Immunother. Cancer 2019). Our recent work has found that immunotherapy with cDC1s in established tumors (both in adjuvant and particularly in neoadjuvant setting) are very effective in generation of memory, which prevents tumor relapse. Notably, cDC1s lead to the generation of a CD4+ T resident memory population which could play a key role in anti-cancer response (Heras-Murillo et al. Nat. Commun. 2025). Our experimental and innovative work in this area has been also highlighted with the opportunity to contribute to two highly cited reviews (Wculek et al. Nat. Rev. Immunol. 2019; Heras-Murillo et al. Nat. Rev. Clin. Oncol. 2024).

My main motivation to work as an immunologist is the translation of our results. This involves collaboration with companies active in the generation of new immunotherapies. We have collaborated with several companies (Medimmune, Miltenyi Biotec, Adendra Therapeutics and Inmunotek). The collaboration with Adendra Therapeutics was focused on DC immunotherapy. Another topic of high interest in our collaboration is the induction of trained immunity, epigenetic changes associated with innate cells of the immune system that improve their secondary response. Our collaboration with Inmunotek S.L. (Alcalá de Henares) is focused on this area. We demonstrated that some of their polybacterial preparations (MV130) work through the induction of trained immunity and we are interested in further finding the mechanisms and new potential applications of these reagents (Saz-Leal et al. Cell Rep 2018a, Martínez-López et al. Immunity 2019, del Fresno et al. Front Immunol 2021, Brandi et al. Cell Rep 2022, Robles-Vera et al. Immunity 2025). In the last years, we have also become interested in research into microbial metabolites that can affect our physiology and response to pathology (Mastrangelo et al. Nature. 2025). We are addressing the interaction of these metabolites with immune cells for immunomodulation. Our interest in microbial signals and metabolites that could boost immunity for the translational development of improved therapies has received the recent support of an ERC Proof of Concept grant (2024).

In the search for new strategies for immunotherapy, our group is exploring and leading a new approach to the manipulation of the immune system based on the emerging field of immuno-metabolism. This research proposal was funded by the European Commission's excellence program (ERC Consolidator Grant, 2016). Our recent results show that the detection of signals through the receptors of the innate immune system leads to the modification of mitochondrial metabolism (Garaude et al. Nat Immunol 2016). Metabolism also affects the differentiation of DCs (Hernández-García et al. Cell Mol Immunol 2022) and macrophages (Izquierdo et al. Cell Rep 2018b), their polarization to promote inflammatory responses (Acín-Pérez et al. Nat Metab 2020) and their function in tissues in homeostasis and upon inflammation (Wculek et al. Immunity, 2023).

Together, these research directions aim to uncover fundamental principles of immune regulation, while translating this knowledge into innovative strategies to combat disease.