Journal for immunotherapy of cancer · 2026
Targeting endosomal trafficking-mediated antigen escape to resensitize myeloma to CAR-T therapy.
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Wang Zhuning, Wang Guanli, Liu Yujie, Zhao Yufei, Guo Shushan, Yang Yicun, Zhang Qikai, Hu Chaolu, Chang Shuaikang, Wu Xiaosong, An Dong, Hu Huifang, Cai Haiyan, Zhang Li, Shi Jumei
Аннотация
BACKGROUND: Antigen escape is one of the leading causes of relapse following chimeric antigen receptor (CAR)-T therapy, particularly in multiple myeloma. A critical gap persists in understanding the tumor-intrinsic pathways that trigger antigen loss, insight essential for devising strategies to resensitize tumors to immune attack. We identify a previously uncharacterized post-translational mechanism centered on the metabolic enzyme ribonucleotide reductase subunit M2 (RRM2), termed trafficking-mediated antigen escape, to enhance cellular therapy efficacy.
METHODS: We combined single-cell RNA sequencing analysis with multiplex immunofluorescence to identify a clinically relevant RRM2+ myeloma subpopulation exhibiting low MICA/B abundance. Functional validation included induced pluripotent stem cell-derived myeloma organoids monitored by real-time imaging and disseminated xenograft models to assess the effect of subtoxic osalmid treatment on NKG2D CAR-T cell activity. Co-immunoprecipitation, guanosine 5'-triphosphate pulldown, and confocal microscopy were used to investigate the underlying trafficking mechanism.
RESULTS: Single-cell analysis uncovered a clinically prevalent RRM2+ myeloma subpopulation with profoundly reduced MICA/B surface abundance, which established tumor-intrinsic heterogeneity as one of fundamental causes of NKG2D CAR-T resistance. We further demonstrated RRM2's non-canonical role as a trafficking regulator that actively shuttles MICA/B toward lysosomal degradation via RAB7A activation while simultaneously blocking RAB11-mediated recycling. Therapeutic intervention using subtoxic osalmid, a clinically approved drug and previously characterized as an RRM2 inhibitor, successfully reversed this trafficking defect, restored MICA/B membrane presentation and synergized with NKG2D CAR-T cells to enhance their expansion, polyfunctional cytokine secretion, and stem-like properties. This combination strategy achieved durable tumor remission in vivo by sustaining T-cell fitness while reducing exhaustion, offering an immediately actionable solution to clinical antigen escape.
CONCLUSIONS: Our study establishes RRM2-driven trafficking as a novel and targetable mechanism of antigen escape in CAR-T therapy. By repurposing osalmid to restore MICA/B surface presentation, we provide a clinically translatable strategy that specifically potentiates NKG2D CAR-T cell efficacy in multiple myeloma and could potentially enhance the efficacy of CAR-T across diverse antigens. This work highlights the therapeutic potential of modulating intracellular trafficking to overcome resistance in cellular immunotherapy.
METHODS: We combined single-cell RNA sequencing analysis with multiplex immunofluorescence to identify a clinically relevant RRM2+ myeloma subpopulation exhibiting low MICA/B abundance. Functional validation included induced pluripotent stem cell-derived myeloma organoids monitored by real-time imaging and disseminated xenograft models to assess the effect of subtoxic osalmid treatment on NKG2D CAR-T cell activity. Co-immunoprecipitation, guanosine 5'-triphosphate pulldown, and confocal microscopy were used to investigate the underlying trafficking mechanism.
RESULTS: Single-cell analysis uncovered a clinically prevalent RRM2+ myeloma subpopulation with profoundly reduced MICA/B surface abundance, which established tumor-intrinsic heterogeneity as one of fundamental causes of NKG2D CAR-T resistance. We further demonstrated RRM2's non-canonical role as a trafficking regulator that actively shuttles MICA/B toward lysosomal degradation via RAB7A activation while simultaneously blocking RAB11-mediated recycling. Therapeutic intervention using subtoxic osalmid, a clinically approved drug and previously characterized as an RRM2 inhibitor, successfully reversed this trafficking defect, restored MICA/B membrane presentation and synergized with NKG2D CAR-T cells to enhance their expansion, polyfunctional cytokine secretion, and stem-like properties. This combination strategy achieved durable tumor remission in vivo by sustaining T-cell fitness while reducing exhaustion, offering an immediately actionable solution to clinical antigen escape.
CONCLUSIONS: Our study establishes RRM2-driven trafficking as a novel and targetable mechanism of antigen escape in CAR-T therapy. By repurposing osalmid to restore MICA/B surface presentation, we provide a clinically translatable strategy that specifically potentiates NKG2D CAR-T cell efficacy in multiple myeloma and could potentially enhance the efficacy of CAR-T across diverse antigens. This work highlights the therapeutic potential of modulating intracellular trafficking to overcome resistance in cellular immunotherapy.