![]() Also fibroblasts, the major constituents of the tumor stroma, take part actively to the tumor-immune cell crosstalk. But immune cells can also induce immunosuppression and support tumor growth, as in the case of regulatory T (T reg) cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs) ( 6, 7, 10, 11). Cytotoxic CD8 + T cells are the primary effectors of natural and therapy-induced anticancer immunity, as they can specifically recognize and kill malignant cells displaying neoantigens (i.e., tumor-specific antigens generated from the expression of mutated genes) ( 9). Tumor-infiltrating immune cells play a pivotal role in tumor control and response to therapy ( 6– 8). The TME is a complex ecosystem composed of various cell types, their secreted products (e.g., cytokines, chemokines), and other non-cellular components of the extracellular matrix (ECM) However, as ICBs are ineffective for most patients ( 2, 3), there is a pressing need to elucidate the mechanisms taking place in the tumor microenvironment (TME). ICBs targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have shown unprecedented durable responses and are now part of the standard of care for patients with different cancer types ( 1). So far, immune checkpoint blockers (ICBs), i.e., monoclonal antibodies targeting immune-cell regulators to boost antitumor immunity, represent the most successful treatment regimens for solid cancers. In recent years, cancer immunotherapy has revolutionized the treatment of human malignancies: from directly killing tumor cells, to supporting the body's own immune system in the fight against cancer. These developments are fundamental to overcome the current limitations of targeted agents and checkpoint blockers and to bring long-term clinical benefits to a larger fraction of cancer patients. We discuss how this broader vision of the cellular heterogeneity and plasticity of tumors, which is emerging thanks to these methodologies, offers the opportunity to rationally design precision immuno-oncology treatments. These include approaches for the characterization of the different cell phenotypes and for the reconstruction of their spatial organization and inter-cellular cross-talk. In this Mini Review, we give an overview of the methodologies that allow studying the heterogeneity of the TME from multi-omics data generated from bulk samples, single cells, or images of tumor-tissue slides. However, as checkpoint blockade is currently beneficial only to a limited fraction of patients, there is an urgent need to understand the mechanisms orchestrating the immune response in the TME to guide the rational design of more effective anticancer therapies. The striking responses obtained with immune checkpoint blockers, i.e., antibodies targeting immune-cell regulators to boost antitumor immunity, have demonstrated the enormous potential of anticancer treatments that target TME components other than tumor cells. The tumor microenvironment (TME) is a multifaceted ecosystem characterized by profound cellular heterogeneity, dynamicity, and complex intercellular cross-talk. 2Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands. ![]() 1Biocenter, Division for Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.Francesca Finotello 1 * Federica Eduati 2 ![]()
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