A Comprehensive Exploration of Agents Targeting Tumor Microenvironment: Challenges and Future Perspectives

Abstract

The tumor microenvironment (TME) encompasses the complex and diverse surroundings in which tumors arise. Emerging insights highlight the TME's critical role in tumor development, progression, metastasis, and treatment response. Consequently, the TME has attracted significant research and clinical interest, leading to the identification of numerous novel therapeutic targets. Advances in molecular technologies now enable detailed genomic and transcriptional analysis of cancer cells and the TME and the integration of microenvironmental data to the tumor genomic landscape. This comprehensive review discusses current progress in targeting the TME for drug development, addressing associated challenges, strategies for modulating the pro-tumor microenvironment, and the discovery of new targets.

Keywords: challenges; mechanisms; resistance; targets; tumor microenvironment.

Figure 1

The tumor microenvironment components. The tumor microenvironment is a complex network of diverse cells and secreted factors that serve as targets for anticancer treatments. It includes various cell types like cancer cells, immune cells (such as T and B lymphocytes, TAMs, DCs, NK cells, myeloid-derived suppressor cells, neutrophils, and eosinophils), stromal cells (like CAFs, pericytes, and mesenchymal stromal cells), as well as vascular networks and tissue-specific cells such as neurons and adipocytes. These cells release components like ECM, growth factors, cytokines, and EVs, crucial for communication within the TME and beyond. CAF: cancer-associated fibroblast; DC: dendritic cell; ECM: extracellular matrix; NK: natural killer; TAM: tumor-associated macrophage; TME: tumor microenvironment.

Figure 2

Cold and hot tumor environment and strategies to turn cold tumors into hot tumors. The primary cellular components and molecular interactions influencing the cold tumor phenotype and the hot tumor phenotype are delineated below. Key abbreviations include the following: NK (natural killer cells), DCs (dendritic cells), pDC (plasmacytoid dendritic cells), M2 (type 2 macrophages), MDSC (myeloid-derived suppressor cells), T eff (effector T cells), T reg (regulatory T cells), TCR (T-cell receptor), MHC (major histocompatibility complex), CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), LAG3 (lymphocyte activation gene-3), PD-1 (programmed cell death-1), and PD-L1 (programmed cell death-ligand 1). On the second table of the figures, we can see an overview of potential strategies to transform cold tumors into hot ones, along with their mechanisms of action, enhancing therapeutic outcomes when combined with immunotherapy.

Figure 3

Mechanisms of action of therapies in TME. Summary of experimental and clinical interventions targeting tumoral stromal components. Tumor development is associated with intrinsic extracellular matrix modifications and cellular components that foster neoplastic progression. Tumor cells can induce pro-tumoral phenotypic changes in macrophages, fibroblasts, and lymphocytes by releasing soluble mediators (depicted as small colored circles). Tumors also release pro-angiogenic factors to guide the migration of vascular cells that form new branched vessels. Several strategies have been developed to disrupt tumor-stromal interactions and enhance immune cell-mediated tumoral attack: ¹Activating DCs with CG-CSF, CD40, and FLT3 agonists to enhance antigen presentation. Another strategy involves administering DC vaccines or a pool of autologous mononuclear cells presenting antigens extracted from tumors and enhanced in vitro (Sipuleucel). ²Augment anti-tumoral cytotoxic lymphocyte activities by introducing CAR T cells or an autologous pool of polyclonal lymphocytes extracted from tumors and enhanced in vitro (Lifileucel). ³Suppression of Treg cell activities using sunitinib, checkpoint inhibitors, or cyclo-phosphamide treatments. ⁴Inhibition of CAFs using mesothelin antibodies in experimental models. ⁵Inhibition of the angiogenic process at various stages by targeting soluble mediators with anti-VEGF agents, blocking their receptors with multi-tyrosine kinase inhibitors, or perturbing downstream signaling using mTOR inhibitors. ⁶Manipulate macrophage polarization toward a proinflammatory and anti-tumoral phenotype by administering TLR-8/9 agonists, CD40 agonists, or CSFR1 inhibitors. CSFR-1: colony-stimulating factor-1 receptor; CAFs: cancer-associated fibroblasts; CAR T cell: chimeric antigen receptor T cells; DCs: dendritic cells; CG-CSF: granulocyte-macrophage colony-stimulating factor; CSF-1R: colony-stimulating factor-1 receptor; CTLs: CD8 positive cytotoxic T lymphocytes; EGF: epidermal growth factor; FGF: fibroblast growth factor;FLT3: FMS-like receptor tyrosine kinase-3; M1: macrophages type 1; M2: macrophages type 2; PDGF: platelet-derived growth factor; Treg: T regulatory cells; TLR-8/9: Toll-like receptors 8 and 9; VEGF: vascular endothelial growth factor.