Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies

SIMPLE SUMMARY: The tumor microenvironment comprises numerous different cellular players that engage transformed cancer cells and may exert pro- vs anti-tumor functions. Their crosstalk, functionality, as well as cell recruitment to cancer lesions, is chiefly dictated by cytokines/chemokines-receptor pairs and these axes can represent therapeutic vulnerabilities—as for immune checkpoint blockers. In this review, we recapitulate the main drivers of cellular TME dynamics, interactions, and functionality, mainly focusing on T lymphocytes, macrophages and cancer associated fibroblasts, also providing an outlook on state-of-the-art TME-targeting agents. ABSTRACT: Cancers are composed of transformed cells, characterized by aberrant growth and invasiveness, in close relationship with non-transformed healthy cells and stromal tissue. The latter two comprise the so-called tumor microenvironment (TME), which plays a key role in tumorigenesis, cancer progression, metastatic seeding, and therapy resistance. In these regards, cancer-TME interactions are complex and dynamic, with malignant cells actively imposing an immune-suppressive and tumor-promoting state on surrounding, non-transformed, cells. Immune cells (both lymphoid and myeloid) can be recruited from the circulation and/or bone marrow by means of chemotactic signals, and their functionality is hijacked upon arrival at tumor sites. Molecular characterization of tumor-TME interactions led to the introduction of novel anti-cancer therapies targeting specific components of the TME, such as immune checkpoint blockers (ICB) (i.e., anti-programmed death 1, anti-PD1; anti-Cytotoxic T-Lymphocyte Antigen 4, anti-CTLA4). However, ICB resistance often develops and, despite the introduction of newer technologies able to study the TME at the single-cell level, a detailed understanding of all tumor-TME connections is still largely lacking. In this work, we highlight the main cellular and extracellular components of the TME, discuss their dynamics and functionality, and provide an outlook on the most relevant clinical data obtained with novel TME-targeting agents, with a focus on T lymphocytes, macrophages, and cancer-associated fibroblasts.