Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights

Abstract

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies.

Keywords: Gastrointestinal Cancers; Immune Landscapes; Metabolic Reprogramming; Targeted Therapies; Tumor Microenvironment.

Figure 1:

Tumor microenvironment regulation of GI tumor initiation and progression. The TME includes diverse cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), immune cells, endothelial cells (EC), and microbiome. These cellular components secrete several growth factors, cytokines, and chemokines supporting tumor growth. Further, the cancer cells secrete several molecules (like cytokines and chemokines) that modulate the TME components. Created with Biorender.com.

Figure 2:

Complex interplay between the primary tumor and immune cells. Cancer and stromal cells secrete chemokines and cytokines to recruit immunosuppressive cells, including tumor-associated macrophages and neutrophils, MDSCs, dendritic cells (DCs), and T cells. Secretome from tumor cells and stromal cells induces the switch (or polarization) of normal immune cells (such as M1 macrophage and N1 neutrophils) to tumor-promoting immune cells (M2 macrophage and N2 neutrophils). These immunosuppressive and cancer cells suppress the cytotoxic function of CD8+ cytotoxic T cells by expressing various factors, such as PD-L1 and B7. The tumor-associated immune cells also secrete various growth factors, cytokines, and chemokines that support tumor and stromal cell growth. The blue line with an arrow at both ends indicates the polarization of the M1 macrophage and N1 neutrophil to the M2 macrophage and N2 neutrophil, respectively. The red line indicates the inhibition. Created with Biorender.com.

Figure 3:

Metabolic reprogramming in GI tumors. GI tumor cells are characterized by enhanced glycolysis, which increases lactate in the microenvironment. An abnormal increase in glucose transporter will lead to a greater glucose uptake. Pyruvate from glycolysis also enters oxidative phosphorylation (TCA cycle) to fuel proliferating cancer cells. Tumor cells increase glutamine uptake from the TME, entering the TCA cycle or de novo nucleotide metabolism or lipid metabolism. Glutamine metabolism enhances the tumor cell-associated signaling MAPK, mTOR, and ERK signaling. TME-derived lipids undergo lipid metabolism, whose intermediates enter the glycolysis and TCA cycle. Abnormal metabolic products from tumor cells support TME cells’ growth and generate immunosuppressive TME. Green arrows indicate upregulation and red arrows indicate downregulation. HK2, PKM, LDH, and FAS depict the potential metabolic enzymes that can be targeted. Blue channels indicate glucose transporters, pink channels indicate lactate transporters and green channels indicate glutamine transporters. Created with Biorender.com.

Figure 4:

Overview of potential targets and related drugs in GI cancer. Targeted therapy acts on various mechanisms and signaling axis of GI cancer, such as immune checkpoints (PD1/PD-L1 and CTLA4), EGFR, HER2, and VEGF, and thus inhibits tumor cell proliferation, differentiation, and invasion. The red lines indicate the binding of targeted therapies to receptors or ligands on the membrane’s outer surface. The blue lines indicate the binding of targeted therapies to signaling molecules in the interior or cytoplasmic side of the cells. Created with Biorender.com.