Advances in targeting tumor microenvironment for immunotherapy

Abstract

The tumor microenvironment (TME) provides essential conditions for the occurrence, invasion, and spread of cancer cells. Initial research has uncovered immunosuppressive properties of the TME, which include low oxygen levels (hypoxia), acidic conditions (low pH), increased interstitial pressure, heightened permeability of tumor vasculature, and an inflammatory microenvironment. The presence of various immunosuppressive components leads to immune evasion and affects immunotherapy efficacy. This indicates the potential value of targeting the TME in cancer immunotherapy. Therefore, TME remodeling has become an effective method for enhancing host immune responses against tumors. In this study, we elaborate on the characteristics and composition of the TME and how it weakens immune surveillance and summarize targeted therapeutic strategies for regulating the TME.

Keywords: cancer; immunosuppression; immunotherapy; targeted; tumor microenvironment.

Figure 1

TME is comprised of different cells and molecules, and the interplay between immunosuppressive cells and tumor cells creates a microenvironment of hypoxia, acidity, high interstitial pressure, tumor-incapacitating angiogenesis, inflammation, and immunosuppression via diverse molecular pathways. (ANG1/2: angiopoietin-1 and 2, IDO: Indoleamine 2,3-dioxygenase, PGE2: prostaglandin E2, CAR-T: chimeric antigen receptor T-cell).

Figure 2

In environments that are both acidic and low in oxygen, transcription of angiogenic factors by HIF stimulates tumor angiogenesis. This progression can be hindered by specific antibodies. (VEGFR: vascular endothelial growth factor receptor, PDGFR: platelet-derived growth factor receptor).

Figure 3

CTLA-4 and PD-1 are expressed on activated T-cells, wherein CTLA-4 competitively antagonizes CD28 and binds to B7-1/2 on the surface of APCs, while PD-1 engages with PD-L1/2 on tumor cells or APCs. Such interactions curtail the proliferation of self-reactive T-lymphocytes and the generation of cytokines.

Figure 4

Gut microbes and their metabolites act on intestinal epithelial cells or bind to their surface pattern recognition receptors, eliciting downstream signaling cascade reflexes that lead to tumor-promoting and anti-tumor immune responses. (NLR1/2: NOD-like receptor 1 and 2, FMT: Fecal microbiota transplant).