Tumor Microenvironment

The tumor microenvironment (TME) critically influences tumor growth, invasion, immune evasion, metastasis, and therapy efficacy as a dynamic ecosystem of immune and stromal cells, extracellular matrix, vasculature, and signaling molecules^[1][2][3].TME promotes tumor immune escape and drug resistance by recruiting immunosuppressive cells (such as Tregs, TAMs), reshaping the metabolic environment (such as lactate accumulation), and forming a dense extracellular matrix (ECM) barrier.

• Cellular components: The TME typically includes a variety of immune cells (dendritic cells, T cells, B cells, NK cells, neutrophils, macrophages) and stromal cells (normal fibroblasts, CAFs, MSCs, inflammatory cells, endothelial cells), as well as tissue-specific cells such as adipocytes and neurons.
• Acellular components: The ECM provides structural support for tumor cells and regulates their migration and invasion. Soluble signaling molecules include chemokines and cytokines (e.g., VEGF, IL-10). Functional particles including exosomes and apoptotic bodies are also present in the TME.

Figure 1. Key mechanisms and interactions in the TME^[1].

The TME fosters tumor resistance and immune evasion through immunosuppression, metabolic reprogramming, and physical barriers. Its composition determines drug absorption, distribution, metabolism, and efficacy, making TME targeting a key anticancer strategy^[4][5][6][7].

Intervention Strategies

• Targeting Immune Checkpoint—— PD-1/PD-L1 inhibitors (e.g., pembrolizumab, nivolumab) relieve T-cell suppression singnals in the TME, restoring their tumor-killing ability; CTLA-4 inhibitors enhance initial T-cell activation. (Learn more about Immune Checkpoint Proteins)

Immunosuppressive cells in the TME (Tregs, CAFs, TAMs, MDSCs, TANs, tDCs) secrete protective factors accelerating tumor progression and weaken immunotherapy.

Intervention Strategies

• Chemotaxis Blockade: CXCR2/CCR2 inhibitors reduce MDSC and TAM recruitment, enhancing T-cell infiltration and PD-1 blockade efficacy.
• Functional Reprogramming: CD40 agonists, TLR7/8 agonists, or CSF-1R inhibitors (e.g., PLX3397) deplete TAMs and inhibit angiogenesis.
• Phagocytosis Enhancement: Targeting SIRPα, LILRB1, or Siglec-10 abrogates “don’t eat me” signals.

In addition, adoptive cell therapies like CAR-T, CAR-NK, and TILs are adoptively transferred antitumor effector cells to reshape the immune landscape^[8].

• Targeting Cytokines: Inhibiting immunosuppressive cytokines or adding stimulatory ones to boost immune cell activity, targeting related receptors for inhibition/activation, can significantly enhance T-cell activation and cytotoxicity, creating a strong synergistic antitumor effect, especially in combination therapies. Examples include the dual-function fusion protein Bintrafusp Alfa (M7824) targeting PD-L1 and TGF-β, intratumoral IL-12 injection, or co-delivery with PD-1/PD-L1 antibodies^[5].

• Enhancing Antigen Presentation: Microtubule inhibitors (e.g., Plinabulin), TLR9 agonists (e.g., SD-101, CMP-001), and oncolytic viruses promote APC maturation, upregulate MHC expression, and release tumor antigens, thereby enhancing antigen presentation and activating antitumor immunity^[9]. These agents are often used in combination with other immunotherapies.

Figure 2. Immunotherapy strategies targeting the TME^[5].

Dense ECM in the TME will prevent immune cell infiltration or drug delivery to the tumor, affecting the efficacy of immunotherapy^[10].

Intervention Strategies

• ECM Remodeling: Targeting collagenases, matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinases (ADAMs) can modulate collagen deposition and degradation, while hyaluronidases (HAase) and hyaluronan (HA) receptors can alter HA levels. In inflammatory and TMEs, CD44-mediated HA signaling pathways are also involved in immune cell activation and tumor cell invasion^[11]. Targeting ECM components not only improves drug delivery efficiency but also promotes immune cell infiltration^[12].(Learn more about MMPs)

Angiogenesis Inhibition. (Learn more about angiogenesis)

TME metabolism is affected by multiple factors, including oncogene-driven intracellular metabolic processes, tissue vascularization, nutrient supply, cytokines, hormones, and metabolites. Tumor cell metabolism can be disrupted by targeting metabolic receptors, metabolic enzymes, or nutrients, thereby effectively inhibiting their proliferation.

Intervention Strategies

• Targeting Metabolic Inhibitory Signals: Targeting Metabolic Inhibitory Signals: TME metabolism is influenced by oncogene-driven intracellular metabolic processes, tissue vascularization, nutrient supply, cytokines, hormones, and metabolites. Targeting metabolic receptors, enzymes, or nutrients can disrupt tumor cell metabolism, effectively inhibiting proliferation. Examples include MCT1 inhibitors (e.g., AZD3965), ACAT1 inhibitors (e.g., Avasimibe), and HIF-1α inhibitors (e.g., IDF-11774), can inhibit abnormal metabolic signaling in the TME^[13][14].

Exosomes and inflammasomes in the TME have dual roles of promoting or suppressing tumors. For example, cancer-derived exosomes create pre-metastatic niches, mediate immune evasion, and induce drug resistance; inflammasomes such as NLRP3 drive inflammation-induced tumorigenesis^[15].

Intervention Strategies

• Utilizing NLRP3 inhibitors (e.g., MCC950) to block inflammasome activity; engineered exosomes (modified with integrins, membrane proteins, etc.) or targeted drug-loaded carriers for precise delivery^[16].

Due to the temporal complexity, spatial heterogeneity, and dependence on peripheral immune system support of the TME, current therapeutic strategies targeting TME still face numerous challenges.