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 ...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.展开更多
Despite compelling preclinical and epidemiological evidence(e.g.,reduced lung cancer incidence in the CANTOS trial),IL-1βinhibition with canakinumab failed to achieve the expected therapeutic effect in the Phase III ...Despite compelling preclinical and epidemiological evidence(e.g.,reduced lung cancer incidence in the CANTOS trial),IL-1βinhibition with canakinumab failed to achieve the expected therapeutic effect in the Phase III clinical trials(CANOPY series)of non-small cell lung cancer(NSCLC).This perspective analyzes the disconnect between mechanistic promise and clinical outcomes.IL-1βdrives NSCLC progression by promoting immunosuppression,angiogenesis,and metastasis.However,CANOPY-2 showed no overall survival(OS)benefit,though a trend emerged in patients with an elevated baseline of high-sensitivity C-reactive protein(hs-CRP).Similarly,CANOPY-1 and adjuvant CANOPY-A missed primary endpoints for progression-free survival(PFS)and disease-free survival(DFS),respectively.These failures highlight limitations of IL-1 monotherapy in advanced,immunosuppressive microenvironments and underscore inadequate patient selection.We propose that IL-1 antagonism retains therapeutic potential but requires refined strategies:biomarker-driven enrichment(e.g.,inflammation signatures like hs-CRP),rational combinatorial regimens informed by successful multi-target agents(e.g.,cadonilimab),and early-stage intervention.Repositioning IL-1 blockers through precision approaches could unlock their value in immuno-oncology.展开更多
文摘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.
文摘Despite compelling preclinical and epidemiological evidence(e.g.,reduced lung cancer incidence in the CANTOS trial),IL-1βinhibition with canakinumab failed to achieve the expected therapeutic effect in the Phase III clinical trials(CANOPY series)of non-small cell lung cancer(NSCLC).This perspective analyzes the disconnect between mechanistic promise and clinical outcomes.IL-1βdrives NSCLC progression by promoting immunosuppression,angiogenesis,and metastasis.However,CANOPY-2 showed no overall survival(OS)benefit,though a trend emerged in patients with an elevated baseline of high-sensitivity C-reactive protein(hs-CRP).Similarly,CANOPY-1 and adjuvant CANOPY-A missed primary endpoints for progression-free survival(PFS)and disease-free survival(DFS),respectively.These failures highlight limitations of IL-1 monotherapy in advanced,immunosuppressive microenvironments and underscore inadequate patient selection.We propose that IL-1 antagonism retains therapeutic potential but requires refined strategies:biomarker-driven enrichment(e.g.,inflammation signatures like hs-CRP),rational combinatorial regimens informed by successful multi-target agents(e.g.,cadonilimab),and early-stage intervention.Repositioning IL-1 blockers through precision approaches could unlock their value in immuno-oncology.
