Immunotherapy in gastrointestinal stromal tumors: Current landscape and future horizons

Table 2 summarizes the basic categories of potential gastrointestinal stromal tumors biomarkers

Type	Biomarker	Clinical relevance	Ref.
Genetic	KIT and PDGFRA mutations	Guide TKI therapy; KIT exon 11 mutations respond well, PDGFRA-D842V mutations show resistance	[58]
Genetic	SDH-deficient/competent GIST	Show resistance to TKIs; alternative treatments required	[58]
Inflammatory biomarker	Neutrophil-to-lymphocyte ratio	High ratio indicates poor prognosis due to increased neutrophil-driven inflammation and reduced lymphocyte-mediated immunity	[53]
Inflammatory biomarker	Systemic immune-inflammation index	Elevated index correlates with tumor progression by promoting pro-tumor inflammation	[48,49]
Immune cell marker	CD8+ T lymphocyte infiltration	Increased CD8+ T cells enhance cytotoxic responses against tumor cells, improving survival	[27,50,52]
Immune cell marker	M2 macrophage infiltration	High M2 macrophages suppress immune responses and promote tumor growth and angiogenesis	[53]
Immune cell marker	B Cell and TLS presence	Dense B cells and TLS formation boost antitumor immunity and predict better immunotherapy response	[59]
Immune checkpoint	PD-L1 expression	Modulates T cell activity; high levels can inhibit immune responses but may predict immunotherapy success	[7,52]
Immune checkpoint	Indoleamine 2,3-dioxygenase	Depletes tryptophan, suppressing T cell function and fostering immune tolerance in the tumor microenvironment	[52-54]]
Immune checkpoint	Tim-3/Gal-9 axis	Tim-3 promotes T cell exhaustion; Gal-9 association linked to reduced CD8+ T cell infiltration	[51]
Tumor antigens	Cancer-testis antigens (NY-ESO-1, MAGE-A3)	Trigger immune responses but are linked to poor TKI response and aggressive tumor behavior	[54,55]
Chemokine biomarker	CXCL13 expression	Attracts B cells to tumor sites, facilitating TLS formation and enhancing immune response	[59]
Immune profiling	Immune clusters (Im-I to Im-IV)	High T cell presence in clusters improves survival; Im-I cluster shows immune evasion via CD276 expression	[47]
Molecular pathway	ERK1/ERK2 pathway activation	Drives tumor proliferation and is linked to immune-poor, aggressive GIST subtypes	[42]
Immune evasion marker	CD276 (B7-H3) expression	Inhibits CD8+ T cell activity, contributing to immune evasion and tumor progression	[43]

GIST: Gastrointestinal stromal tumors; TKI: Tyrosine kinase inhibitors; TLS: Tertiary lymphoid structures.