Immunotherapy in gastrointestinal stromal tumors: Current landscape and future horizons

Abstract

Gastrointestinal stromal tumors (GISTs) feature a unique tumor microenvironment (TME) with abundant immune infiltrates, including CD8+ T cells and tertiary lymphoid structures, alongside significant immune escape mechanisms such as indoleamine 2,3-dioxygenase (IDO) overexpression, MHC I loss, and regulatory T-cell activity. These factors contribute to an immunosuppressive TME, limiting the effectiveness of immune responses. Recent proteomic and immune profiling has identified distinct immune clusters, ranging from highly infiltrated "hot" tumors to immune-desert "cold" tumors, offering new insights into immune heterogeneity and prognostic stratification. While tyrosine kinase inhibitors (TKIs) like imatinib have shown immunomodulatory effects, clinical trials with immune checkpoint inhibitors (ICIs) alone or in combination have yielded modest outcomes. This editorial examines the immunologic landscape of GIST, explores the interplay between ICIs and TKIs, and highlights emerging therapeutic strategies such as IDO inhibition, bispecific antibodies, and patient selection based on TME characteristics. These insights pave the way for more effective immunotherapy approaches in GIST.

Key Words: Gastrointestinal stromal tumors; Tumor microenvironment; Immune checkpoint inhibitors; Biomarker-driven therapy; Immunotherapy strategies

Core Tip: Immunotherapy for gastrointestinal stromal tumors (GISTs) remains an emerging field with promising but early-stage developments. This editorial summarizes the current landscape of immunotherapy in GISTs, focusing on the immune microenvironment, advances in biomarker discovery, and innovative strategies such as immune checkpoint inhibitors, cytokine-based therapies, and adoptive cell therapies. Future directions emphasize the integration of immune profiling and personalized combination therapies to optimize treatment outcomes. Understanding these dynamics will be essential for overcoming resistance and improving precision oncology in GIST management.

INTRODUCTION

According to the latest guidelines, tyrosine kinase inhibitors (TKIs) are the cornerstone of therapeutic management for gastrointestinal stromal tumors (GISTs)[1,2]. Their use is tailored to the tumor's mutational profile, with imatinib serving as the first-line therapy for GISTs harboring KIT or PDGFRA mutations sensitive to this agent. For cases with imatinib-resistant mutations, such as PDGFRA exon 18 D842V, avapritinib is preferred[3]. Subsequent lines of therapy include sunitinib, regorafenib, and ripretinib for patients whose disease progresses on prior TKIs. Dose adjustments and alternative options are employed to manage resistance, highlighting the pivotal role of TKIs across all stages of GIST treatment[3,4]. At present, immunotherapy for GISTs is still in the clinical trial phase and has not yet been adopted into clinical practice. However, there is a growing interest in this approach, as emerging data highlight the potential of targeting the immune microenvironment in GISTs. Table 1 summarizes the results from clinical trials evaluating immunotherapeutic approaches in GIST[5-10].

Table 1 summarizes the results of clinical trials evaluating various immunotherapeutic approaches in gastrointestinal stromal tumors.

Ref.	Treatment	Phase	Number of patients	ORR (%)	Median PFS	Median OS	Discussion
Chen et al[5], 2012	Peg-IFNa2b + Imatinib	II	8	100%	NR (> 3 years)	NR	New PR achieved after reintroduction of Peg-IFNa2b in a patient who progressed on imatinib maintenance therapy
D’Angelo et al[6], 2017	Dasatinib + Ipilimumab	Ib	20	53.8% (by Choi criteria)	2.8 months	13.5 months	7/13 evaluable GISTs had PR by Choi criteria
Toulmonde et al[7], 2018	Pembrolizumab + Cyclophosphamide	II	9	0%	6 months PFS: 11%	-	63% of GISTs showed high IDO expression
Singh et al[8], 2019	Nivolumab +/- Ipilimumab	II	N: 15, N + I: 12	N: 0%, N + I: 8.3%	N: 8.57 weeks, N + I: 9.1 weeks	N:9.1 months, N + I: 12.1 months	Responses and disease control observed, drugs well tolerated
Chen et al[9], 2020	Nivolumab +/- Ipilimumab	II	N: 9, N + I: 9	N: 0%, N + I: 0%	N: 1.5 months, N + I: 2.9 months	-	No confirmed responses in GIST
NCT05152472[10]	Imatinib + Atezolizumab vs Imatinib alone	II	110 (planned)	Ongoing	Ongoing	Ongoing	Trial ongoing to assess PFS improvement with combination therapy
NCT03609424[10]	PDR001 + Imatinib	I/II	39	Not reported	Not reported	Not reported	Not reported

Peg-IFNa2b: Pegylated interferon alpha-2b; PFS: Progression-free survival; OS: Overall survival; ORR: Objective response rate; PR: Partial response; NR: Not reached; IDO: Indoleamine 2,3-dioxygenase; N: Nivolumab; I: Ipilimumab.

ADVANCING GIST IMMUNOTHERAPY THROUGH COMPREHENSIVE IMMUNE PROFILING

Cancer immunotherapy has revolutionized oncology by utilizing the immune system to target and eliminate malignancies, including GISTs[11]. Techniques such as adoptive cell transfer (ACT) and immune checkpoint inhibitors (ICIs) have achieved substantial success, delivering durable responses in a subset of patients. However, the efficacy of these therapies is closely intertwined with the complex and dynamic nature of the tumor microenvironment (TME), particularly the roles and characteristics of tumor-infiltrating immune cells[12,13]. Advances in single-cell technologies, such as single-cell RNA sequencing (scRNA-seq) and mass cytometry, have enabled detailed profiling of the GIST TME, providing insights into the heterogeneity and functional diversity of immune cells within tumors[14,15]. Key findings from recent research underscore the significant roles of cytotoxic T-cells[16,17], regulatory T-cells[18], tumor-associated macrophages (TAMs)[19,20], and other immune populations in shaping the response to immunotherapy in GISTs[18]. For instance, increased presence of cytotoxic CD8+ T-cells often correlates with better responses to ICIs, whereas an abundance of immunosuppressive TAMs and regulatory T-cells may predict resistance to such therapies[15].

The emerging understanding of these immune dynamics informs strategies for enhancing immunotherapy in GISTs. For example, modulating TAM polarization[21], reactivating exhausted T-cells[22], or targeting immune checkpoint proteins such as PD-1/PD-L1 and CTLA-4 have become central to therapeutic innovation[16,23]. Furthermore, the identification of new biomarkers through single-cell analysis can guide patient stratification and improve the precision of immunotherapeutic interventions[7,24]. Imatinib, widely recognized for its role in targeting c-kit and PDGFRa, also exhibits notable immunomodulatory effects in the management of GISTs[14]. Beyond its oncogenic inhibition, imatinib promotes immune activation by reversing M2 macrophage polarization[25], impairing dendritic cell differentiation[26], and enhancing NK cell activity through c-kit inhibition[27]. This leads to increased Th1 responses, CD8+ T-cell infiltration, and a reduction in regulatory T cells and indoleamine 2,3-dioxygenase (IDO) expression, thereby mitigating immune escape and supporting tumor suppression[14]. Overall, the integration of advanced single-cell profiling technologies with clinical research is accelerating progress in GIST immunotherapy.

EMERGING IMMUNOTHERAPY STRATEGIES FOR GIST: TARGETING THE TME

Immunotherapy is a promising strategy in the management of GISTs. The immune microenvironment plays a critical role in GIST progression, and targeting it has been proposed to enhance the effectiveness of therapies like imatinib. Immunotherapeutic strategies for GISTs can be classified into several key categories: Cytokine-based therapies, ICIs, antibody-based treatments, antibody-drug conjugates (ADCs), vaccine-based immunotherapies, and ACTs[14,15].

Cytokine-based therapies, such as pegylated interferon-α-2b (PegIFNα2b), have shown promise in modulating immune responses. In patients with advanced stage III/IV GISTs, the combination of PegIFNα2b and imatinib showed notable immunological and clinical benefits. The therapy enhanced the infiltration of immune cells producing IFN-γ, such as CD4+ and CD8+ T cells and natural killer (NK) cells, into the TME. These immune responses correlated with a 100% overall response rate, highlighting the synergistic potential of using PegIFNα2b alongside imatinib[5]. The combination of Peg-IFNα-2b and imatinib synergistically inhibits proliferation and promotes apoptosis in imatinib-resistant GIST cells by downregulating p-mTOR and Bcl-2 expression, targeting the PI3K/Akt/mTOR pathway. This suggests a potential strategy for overcoming imatinib resistance[28]. ICIs, including anti-PD-1[7-9,29-31]. Anti-PD-L1, and anti-CTLA-4[6,32,33] antibodies, have shown limited success in advanced GIST cases, partly due to the immunosuppressive TME characterized by low PD-L1 expression, high levels of M2 macrophages, and regulatory T cells[14]. However, patients with specific features, such as PDGFRA D842V mutations[34], high PD-L1 expression, or TLS presence, may derive more benefit from these therapies[8]. Early intervention with ICIs or their use in combination with imatinib may further improve their effectiveness.

Antibody-based therapies and ADCs are being developed to target key molecules in GISTs, such as KIT, PDGFRA, and SSTR2. For instance, anti-KIT monoclonal antibodies like SR1 have demonstrated potential in reducing KIT expression and enhancing macrophage-mediated tumor cell death, independent of imatinib sensitivity[35]. Edris et al[36] demonstrated that the anti-KIT monoclonal antibody SR1 effectively inhibited the growth of both imatinib-sensitive and imatinib-resistant GISTs. In vitro, SR1 reduced cell proliferation equally across several GIST cell lines by downregulating cell-surface KIT expression. Additionally, SR1 enhanced macrophage-mediated phagocytosis of GIST cells, indicating an immune-mediated mechanism of tumor clearance[36]. In vivo, SR1 significantly suppressed tumor growth in xenograft models, reducing imatinib-resistant GIST430 tumor size by 10-fold and imatinib-sensitive GIST882 tumors by fivefold. These findings suggest SR1’s dual action—direct KIT inhibition and stimulation of innate immune responses—offers a promising approach for overcoming imatinib resistance in GIST therapy[36]. ADCs, including anti-KIT conjugates like LOP628-DM1 and anti-GPR20 ADCs, have shown efficacy in preclinical models[37], though clinical application remains limited by side effects such as hypersensitivity reactions[38].

Vaccine-based therapies and ACTs are also emerging as innovative approaches. Ilixadencel, an allogeneic dendritic cell vaccine, has shown tumor responses in some GIST patients[39]. Ilixadencel is an allogeneic, cell-based immune primer administered directly into tumors to stimulate an anti-cancer immune response[40]. It releases pro-inflammatory cytokines and chemokines that recruit and activate NK cells and dendritic cells at the tumor site. Activated NK cells kill tumor cells, releasing tumor-associated antigens, while the cytokines from both ilixadencel and NK cells promote the maturation and cross-presentation ability of recruited dendritic cells. These dendritic cells then present the antigens to cytotoxic CD8+ T cells, triggering a systemic immune response against the tumor[40]. Additionally, ilixadencel helps reduce local immunosuppression by inhibiting suppressive cells like regulatory T cells and myeloid-derived suppressor cells[40]. CAR-T cell therapies targeting KIT and other tumor antigens have demonstrated effectiveness in preclinical studies. Adoptive transfer of cytokine-induced killer (CIK) cells has shown promise in overcoming resistance to standard therapies[41]. The therapy functions by utilizing CIK lymphocytes and interferon-alpha (IFN-α) to target KIT/PDGFRA wild-type GIST (wtGIST)[41]. CIK cells eliminate tumor cells through the release of granzyme B and secrete high levels of IFN-α and IFN-γ, which stimulate immune responses. Additionally, CIK cells produce factors that increase the expression of PD-L1/2 and HLA-I on tumor cells, improving their visibility to the immune system[41]. IFN-α independently exerts antitumor effects in certain wtGIST cells, particularly those with elevated IFN receptor expression. Tumor cells that persist after IFN-α exposure remain vulnerable to CIK cell-mediated killing, indicating a synergistic effect between the two treatments[41]. Additionally, novel targets such as M2 macrophages, Treg cells, LAG3, Tim-3, WT1, and CSPG4 are being explored to address immune escape mechanisms in GISTs[14].

ADVANCING IMMUNOTHERAPY IN GIST: INSIGHTS INTO BIOMARKER-DRIVEN STRATEGIES

While these approaches hold significant promise, further refinement of immunotherapy strategies is required. This includes identifying reliable biomarkers for patient selection, and developing personalized combination therapies to optimize immune responses and overcome treatment resistance. Two recent studies provide valuable insights in this direction[22,42]. Petitprez et al[22] explored the significance of B cells and tertiary lymphoid structures (TLSs) in the TME of soft tissue sarcomas, including GISTs, and their impact on survival and immunotherapy outcomes. By analyzing gene expression profiles from 608 samples, five sarcoma immune classes (SICs) were identified, with SIC E standing out for its immune-rich characteristics, including a high density of B cells within TLSs. Notably, tumors with abundant B cell infiltration, as seen in SIC E, were associated with improved overall survival, even when CD8+ T cell levels were low, highlighting the independent prognostic value of B cells. TLSs in SIC E tumors were particularly rich in B cells, T cells, and dendritic cells, and are believed to serve as hubs for generating antitumor immune responses. Additionally, SIC E tumors exhibited a higher response rate to PD1 blockade therapies like pembrolizumab compared to other immune classes, with a 50% objective response rate. This underscores the potential of B cell-rich TMEs to enhance the effectiveness of immunotherapy. Biomarkers such as the presence of TLSs, increased CXCL13 expression, and B cell abundance emerged as critical predictors of response to ICI[22]. Sun et al[42] investigated the proteomic and phosphoproteomic characteristics of GISTs in 193 patients. They identified four distinct immune clusters, each with varying levels of immune and stromal cell infiltration. These clusters demonstrated significant differences in progression-free survival. The first two clusters (Im-I and Im-II) were characterized by higher levels of T-cell infiltration, including CD4+ and CD8+ T cells, and upregulation of antigen-presentation pathways. These clusters showed improved survival outcomes, highlighting the potential protective role of T-cell activity. However, cluster Im-I exhibited elevated levels of CD276, a molecule associated with immune evasion[43], which could suppress CD8+ T-cell activity and suggest potential benefits from therapies targeting immune checkpoint pathways. Cluster Im-III, predominantly associated with high-risk tumors, was enriched in pathways related to ERK1 and ERK2 cascades, indicating a more aggressive tumor biology. In contrast, cluster Im-IV exhibited the lowest immune scores and minimal immune cell infiltration, suggesting a "cold" TME with poor immune engagement. By integrating immune and proteomic clustering, they further refined the classification of stomach GISTs, revealing combinations of immune and molecular profiles that influence prognosis. This analysis underscores the heterogeneity of immune responses in GISTs and highlights the potential for immune-based therapeutic strategies to improve outcomes in specific patient subgroups.

Building on these insights into the TME and immune profiling of GISTs, it is crucial to consider how underlying genetic mutations further shape the immune landscape and influence therapeutic outcomes. KIT-mutant GISTs typically show lower levels of immune cell infiltration, including CD8+ T lymphocytes and NK cells, and exhibit reduced expression of MHC-I molecules, contributing to immune evasion and potentially limiting the efficacy of immunotherapies[27,44]. Conversely, PDGFRA-mutant GISTs, particularly those with the D842V mutation, demonstrate a more immunogenic profile with higher infiltration of CD8+ T cells, NK cells, and dendritic cells, along with increased expression of immune checkpoint molecules such as PD-L1 and IDO[34,44]. This enhanced immune surveillance correlates with better clinical outcomes and suggests a potential for improved responsiveness to ICIs[34,44,45]. In contrast, KIT/PDGFRA-wild-type GISTs, which include succinate dehydrogenase (SDH)-deficient and SDH-competent subtypes, present a more complex immune landscape. SDH-deficient GISTs often exhibit a pronounced immunosuppressive microenvironment characterized by low levels of MHC-I expression and minimal infiltration of cytotoxic immune cells, which may contribute to their resistance to both TKIs and immunotherapy[44]. Some studies suggest that KIT/PDGFRA-WT GISTs may have varying degrees of immune cell infiltration, with conflicting reports on the abundance of CD3+, CD4+, and CD8+ T cells. While Sun et al[46] reported increased CD8+ T cell infiltration in WT GISTs compared to KIT- and PDGFRA-mutant tumors, Gasparotto et al[44] found reduced T cell infiltration and lower expression of MHC-I and immune checkpoint molecules in WT GISTs, highlighting the heterogeneity within this subgroup. These differences in immune cell infiltration and checkpoint molecule expression have important prognostic implications and may influence the effectiveness of emerging immunotherapeutic strategies.

Beyond genetic drivers, systemic inflammatory biomarkers like the neutrophil-to-lymphocyte ratio[47], platelet-to-lymphocyte ratio, and systemic immune-inflammation index have emerged as prognostic indicators, correlating with tumor progression, recurrence risk, and treatment response[48,49]. The TME also plays a pivotal role, with high infiltration of CD8+ T lymphocytes and NK cells associated with favorable outcomes, while increased M2 macrophage and Treg infiltration contribute to immunosuppression and poorer prognosis[27,50,51]. In addition to traditional biomarkers, the expression of immune checkpoint molecules such as PD-L1, IDO, and Tim-3 has gained attention for their prognostic and therapeutic implications in GIST management. Although PD-L1 expression shows variability, some studies suggest that higher levels correlate with improved recurrence-free survival (RFS), while others associate it with resistance to therapy, underscoring the complexity of its role[7,46,52]. Similarly, elevated IDO expression driven by KIT signaling contributes to an immunosuppressive microenvironment, and its inhibition has shown promise in enhancing the efficacy of imatinib and PD-1 blockade in preclinical models[52,53]. Furthermore, the presence of cancer-testis antigens, such as NY-ESO-1 and MAGE-A3, in 26.7%-40% of GISTs has been linked to poor responses to TKIs and shorter RFS, suggesting their potential as biomarkers for aggressive disease and targets for immunotherapy[54,55]. Finally, GISTs generally exhibit a low tumor mutation burden (TMB), though more aggressive forms show increased genomic alterations like copy number changes and structural variants[56]. Despite the low TMB, certain mutations can lead to the formation of neoantigens. For instance, the KIT A502_Y503 duplication mutation, frequently observed in Chinese GIST patients, results in neoantigen peptides that strongly bind to MHC class I molecules. This mutation, present in around 16% of cases, is often linked to reduced sensitivity to imatinib, but it opens the door for neoantigen-targeted immunotherapies as a potential treatment strategy[57].

These insights highlight the growing importance of integrating molecular, immunological, and systemic biomarkers into personalized GIST management strategies. The above is briefly summarized in Table 2[58,59].

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.

The above emphasize the potential of immune profiling and biomarker discovery to enhance immunotherapy outcomes, offering a path toward more precise and effective treatments for GISTs.

CONCLUSION

While early findings from small, retrospective studies are encouraging, validation through large-scale, prospective research is essential to confirm these results. Future investigations should focus on longitudinal studies to evaluate the long-term efficacy and safety of PD-1/PD-L1 inhibitors and IDO-targeted therapies, particularly in combination with established TKIs[60]. IDO1 inhibitors were explored as a strategy to overcome resistance to immune checkpoint inhibitors by targeting tryptophan metabolism and reducing immunosuppression in the tumor microenvironment[61]. While early trials showed promise[62-64], phase 3 studies[65], including the KEYNOTE-252/ECHO-301 trial, failed to demonstrate clinical benefit[60,66]. The heterogeneity of IDO1 expression and the activation of compensatory pathways, such as AhR and TDO2, may have contributed to these failures[60]. Moreover, exploring the role of M2 TAM polarization and its influence on treatment outcomes remains a critical area for further research. Biomarker-driven approaches, including comprehensive immune profiling and proteomics, offer great potential for identifying novel biomarkers such as B cells and TLSs within the GIST immune microenvironment. These biomarkers could guide more personalized treatment strategies by taking into account the tumor’s immune characteristics and levels of immune cell infiltration. For example, bispecific antibodies (bsAbs) represent a promising class of immunotherapies designed to engage multiple targets simultaneously, enhancing precision and efficacy in cancer treatment[67]. While their success has been particularly evident in hematologic malignancies[68], their application in GISTs, remains an area of active investigation. GISTs are primarily driven by KIT and PDGFRA mutations, with targeted TKI like imatinib being the standard treatment[58]. However, resistance to TKIs often emerges, necessitating alternative therapeutic strategies. Bispecific antibodies could potentially offer a novel approach by leveraging immune activation against GIST cells[67]. For instance, a bsAb targeting KIT-expressing tumor cells while engaging T cells via CD3 could promote direct immune-mediated cytotoxicity[69]. Alternatively, bispecific antibodies that combine checkpoint inhibition with tumor antigen targeting might enhance the immune response within the typically immunosuppressive GIST microenvironment[70]. However, their integration into clinical practice will require robust validation through large, multi-center clinical trials to refine patient selection and optimize immunotherapy outcomes. Ultimately, the successful application of these biomarkers has the potential to significantly improve the precision and effectiveness of GIST treatments, leading to more tailored therapeutic interventions and better outcomes for patients.