arXiv:2604.05478q-bio.GNcs.LG2026-04

现有肿瘤免疫治疗预测模型跨队列表现差,难以可靠应用。

Transcriptomic Models for Immunotherapy Response Prediction Show Limited Cross-cohort Generalisability

  • 对比九种转录组模型,检验其在独立数据集上的预测能力。
  • 多数模型表现仅略高于随机水平,单细胞模型改进有限。
  • 模型间生物信号不一致,提示需更统一的预处理与设计标准。

免疫检查点抑制剂(ICIs)已革新癌症治疗,但大量患者存在原发或获得性耐药,精准的治疗前反应预测仍是未满足的需求。基于批量和单细胞RNA测序(scRNA-seq)的转录组生物标志物为捕捉肿瘤-免疫互作提供了前景,但现有预测模型的跨队列泛化能力尚不明确。我们系统评估了九种前沿转录组ICIs反应预测模型:五种基于批量RNA-seq(COMPASS、IRNet、NetBio、IKCScore、TNBC-ICI),四种基于scRNA-seq(PRECISE、DeepGeneX、Tres、scCURE),使用开发过程中未见的公开独立数据集进行测试。总体而言,预测性能平庸:批量RNA-seq模型在多数队列中表现接近随机水平,而单细胞模型仅略有提升。通路层面分析显示,各模型间生物标志信号稀疏且不一致。尽管基于scRNA-seq的模型趋同于移植物排斥等免疫相关程序,批量模型则缺乏可重现的重叠。PRECISE和NetBio识别出最连贯的免疫相关主题,而IRNet主要捕获代谢通路,与ICIs生物学关联弱。这些发现表明当前转录组预测模型跨队列鲁棒性和生物一致性均有限,亟需改进领域自适应、标准化预处理及基于生物学机制的模型设计。

原文摘要 · Abstract (English)

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; yet substantial proportion of patients exhibit intrinsic or acquired resistance, making accurate pre-treatment response prediction a critical unmet need. Transcriptomics-based biomarkers derived from bulk and single-cell RNA sequencing (scRNA-seq) offer a promising avenue for capturing tumour-immune interactions, yet the cross-cohort generalisability of existing prediction models remains unclear.We systematically benchmark nine state-of-the-art transcriptomic ICI response predictors, five bulk RNA-seq-based models (COMPASS, IRNet, NetBio, IKCScore, and TNBC-ICI) and four scRNA-seq-based models (PRECISE, DeepGeneX, Tres and scCURE), using publicly available independent datasets unseen during model development. Overall, predictive performance was modest: bulk RNA-seq models performed at or near chance level across most cohorts, while scRNA-seq models showed only marginal improvements. Pathway-level analyses revealed sparse and inconsistent biomarker signals across models. Although scRNA-seq-based predictors converged on immune-related programs such as allograft rejection, bulk RNA-seq-based models exhibited little reproducible overlap. PRECISE and NetBio identified the most coherent immune-related themes, whereas IRNet predominantly captured metabolic pathways weakly aligned with ICI biology. Together, these findings demonstrate the limited cross-cohort robustness and biological consistency of current transcriptomic ICI prediction models, underscoring the need for improved domain adaptation, standardised preprocessing, and biologically grounded model design.

免疫治疗转录组预测模型泛化能力

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