06147595

June 28, 2025, 07:31

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Dear Editor, I read with great interest the editorial by Papadakos et al. on the evolving immunotherapeutic landscape in gastrointestinal stromal tumors (GISTs). The authors provide a comprehensive overview of the tumor microenvironment (TME), challenges in immunotherapy response, and emerging strategies. I would like to offer several complementary insights and suggest future directions for translational and clinical research. 1. Stratifying GISTs Through Immune Profiling: The authors rightly emphasize the immunosuppressive TME in GISTs. Building on this, emerging evidence from proteomic and transcriptomic studies supports the existence of distinct immune clusters ranging from inflamed “hot” tumors (TLS⁺/B-cell-rich) to immune-desert “cold” phenotypes. These immune subtypes have shown clear prognostic and predictive value for checkpoint inhibitor response, with objective response rates reaching 50% in TLS-rich subgroups. Integration of spatial profiling and CXCL13 expression as biomarkers may refine patient selection for PD-1/PD-L1 blockade. 2. 2. Rationale for Combination Strategies: While the editorial correctly notes the modest activity of ICIs in unselected patients, combinatorial approaches offer promise. For example, pegylated interferon-alpha-2b (PegIFNα2b) in conjunction with imatinib significantly enhances immune infiltration and suppresses PI3K/mTOR signaling, achieving remarkable response rates in early trials. Similarly, imatinib’s ability to reverse immunosuppression via IDO downregulation and Treg reduction provides a mechanistic rationale for synergy with ICIs, particularly in PDGFRA D842V-mutant GISTs. 3. Targeting Tumor Antigens and TME Components: Antibody-based therapies like SR1 (anti-KIT) have demonstrated macrophage-dependent cytotoxicity even in imatinib-resistant models. This offers a novel route to bypass TKI resistance. Additionally, novel modalities such as bispecific antibodies targeting KIT or PDGFRA in conjunction with CD3⁺ T cell engagement may overcome immune exclusion in “cold” tumors. 4. Addressing IDO Inhibitor Failures: The editorial notes the challenges with IDO1-targeted therapies. We propose that resistance may stem from spatial heterogeneity and compensatory activation of AhR and TDO2 pathways. Poly-pathway blockade, rather than IDO inhibition alone, may be essential to overcome this resistance. 5. Moving Forward: Future success in GIST immunotherapy will depend on Immune subtyping based on TLS, B cell density, and proteomic clusters (Im-I to Im-IV), Rational combination trials of TKIs + ICIs ± TME-modifying agents, Validation of biomarkers such as CXCL13, CD276, and KIT-derived neoantigens in prospective cohorts. In conclusion, the editorial provides an excellent foundation for discourse. We advocate for multi-center, biomarker-driven clinical trials to translate these emerging insights into tailored immunotherapy regimens for GIST patients. Sincerely, Fen Wang Oncology Department, Peking University Shenzhen Hospital.

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