The Tumor Microenvironment: A Pro-Tumor Niche and Therapeutic Target in Cancer

Cancer is not a single mass of cancer cells, but a complex ecosystem, the tumor microenvironment (TME). TME is a local steady-state environment composed of tumor cells, immune cells, stromal cells, and non-cellular components including the blood and lymphatic vascular networks, extracellular matrix, various signaling molecules (such as cytokines and chemokines), and physicochemical characteristics (such as hypoxia and acidity)^[1].

The tumor microenvironment (TME) dominates the malignant progression of tumors. It not only directly supports cancer cell growth, proliferation, invasion, and metastasis, but also maintains key biological processes such as cancer stem cells (CSCs), promotes angiogenesis, and inhibits apoptosis. Furthermore, the TME is a core factor mediating tumor cell immune evasion and therapeutic resistance. In summary, The TME provides tumors with continuous growth signals that can mimic oncogene activation, inactivate tumor suppressor genes, and hijack normal stromal support functions^[2]. 
Immune cells are the most abundant non-cancerous cells in the TME. Tumor-associated macrophages (TAMs), for example, expand through in situ proliferation and recruit monocyte-derived macrophages (MDMs) into the TME for recruitment, inducing TAM differentiation into a tumor-promoting phenotype. TAMs promote tumorigenesis through inflammation and enhance subsequent tumor growth and metastasis through immune evasion, angiogenesis, cancer cell invasion, and immunosuppression. Furthermore, TAMs can influence cancer recurrence after conventional treatment. Interventions targeting signaling pathways such as PD-L1/PD-1, CSF1R, CCL2/CCR2, and the CD47/SIRPα complex can modulate TAM function, offering potential benefits for cancer therapy. Tumor growth requires supplementary blood supply to deliver oxygen and nutrients. Angiogenesis involves interactions between endothelial cells and pericytes and multiple growth factor signaling pathways such as PDGF-B/PDGFRβ, VEGF-A/VEGFR2, and ANG2-Tie-2 systems. The basement membrane (BM)/extracellular matrix (ECM) remodeling is mediated by multiple families of matrix-degrading enzymes, including cysteine, serine, and MMP proteases. Altered intratumoral environmental conditions caused by matrix changes can reduce the effective delivery of anticancer drugs. Controlled BM/ECM degradation can inhibit angiogenesis and tumor cell invasion into surrounding normal tissues, as well as the blood and lymphatic systems. Cancer-associated fibroblasts (CAFs), as the most abundant stromal cells, significantly promote tumor growth and metastasis by physically remodeling the ECM and secreting cytokines such as IL-6, CXCL12, and VEGFA^[3][4].
Currently, the TME plays a key role in regulating the efficacy of cancer treatments. Targeting immune cells such as TAMs, dendritic cells (DCs) and T cells, tumor vasculature, ECM and CAFs has emerged as a major strategy for enhancing treatment outcomes and holds significant potential for clinical translation.