Molecular characteristics and immune microenvironment of gastrointestinal stromal tumours: targets for therapeutic strategies

Abstract

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours, arising mainly from the interstitial cells of Cajal (ICCs) of the gastrointestinal tract. As radiotherapy and chemotherapy are generally ineffective for GISTs, the current primary treatment is surgical resection. However, surgical resection is not choice for most patients. Therefore, new therapeutic strategies are urgently needed. Targeted therapy, represented by tyrosine kinase inhibitors (TKIs), and immunotherapy, represented by immune checkpoint inhibitor therapies and chimeric antigen receptor T-cell immunotherapy (CAR-T), offer new therapeutic options in GISTs and have shown promising treatment responses. In this review, we summarize the molecular classification and immune microenvironment of GISTs and discuss the corresponding targeted therapy and immunotherapy options. This updated knowledge may provide more options for future therapeutic strategies and applications in GISTs.

Keywords: gastrointestinal stromal tumours; immune microenvironment; immunotherapy; molecular characteristics; targeted therapy.

Figure 1

Overview and approximate percentage of molecular typing of genes driving GISTs.

Figure 2

Genetic characteristics and molecular classification of induced GISTs.

Figure 3

Aberrant genetic alterations in GISTs activate multiple signalling cascades thereby preventing apoptosis and promoting cell survival and proliferation.

Figure 4

From gene mutation to clinical refractory GISTs, the corresponding site mutation type, the sensitivity changes of imatinib, and the targeted drugs at each stage.

Figure 5

The main immune infiltrating cells and corresponding functions of GISTs microenvironment.

Figure 6

(A) Immune checkpoint inhibition-dependent anti-GISTs immunotherapy and corresponding inhibitors. (B) ST3GAL1 inhibits the localization of CAR-T cells to tumour sites, whereas βII-spectrin enhances the localization of CAR-T cells to tumour sites. (C) DS-6157a targets non-tyrosine kinases GPR20 to inhibit the immunotherapy of drug-resistant GISTs.