Scholarlink

<p>Gastrointestinal (GI) cancers account for nearly one-third of cancer-related deaths worldwide and often remain difficult to treat because of pronounced molecular heterogeneity and strongly immunosuppressive tumor microenvironments (TMEs). Antibody–drug conjugates (ADCs) deliver highly potent cytotoxic payloads to antigen-positive cells and may partially address intratumoral heterogeneity through bystander killing. In contrast, immunofusion proteins (IFPs)—including cytokine–antibody fusions and T-cell–redirecting modalities such as bispecific T-cell engagers—are designed to localize immune activation and/or retarget immune effectors within immunologically “cold”, stroma-rich tumors. In this review, we integrate recent clinical and translational advances in ADCs and emerging IFP platforms across gastric, colorectal, pancreatobiliary and hepatocellular cancers, with particular attention to organ-dependent efficacy–toxicity trade-offs (e.g., interstitial lung disease (ILD) associated with DXd-based ADCs; cytokine release syndrome with T-cell engagers) and convergent resistance mechanisms, including antigen loss, impaired payload processing, immune exhaustion, and stromal exclusion. We further propose “immunocytotoxic convergence” as a hypothesis-generating and testable working model: under specific conditions, ADC-driven cytoreduction, immunogenic stress signatures consistent with immunogenic cell death (ICD), and/or stromal remodeling may transiently improve immune accessibility and thereby create a window for subsequent immune amplification by IFPs. Direct clinical evidence for an explicit ADC→IFP Prime–Amplify sequence in GI cancers remains limited. We therefore summarize the current evidence base, define key failure modes and safety constraints, and outline biomarker-enabled experimental and early-phase trial approaches needed to validate—or falsify—this sequencing concept.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Immuno-cytotoxic convergence: integrating antibody‒drug conjugates and immunofusion proteins to overcome resistance in gastrointestinal cancers

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

查看全文
  • Shenghong Wu,
  • Ran Cui,
  • Kangnan Zhao,
  • Zhen Yang,
  • Zihan Yi,
  • Weiwei Cao,
  • Li Ye

摘要

Gastrointestinal (GI) cancers account for nearly one-third of cancer-related deaths worldwide and often remain difficult to treat because of pronounced molecular heterogeneity and strongly immunosuppressive tumor microenvironments (TMEs). Antibody–drug conjugates (ADCs) deliver highly potent cytotoxic payloads to antigen-positive cells and may partially address intratumoral heterogeneity through bystander killing. In contrast, immunofusion proteins (IFPs)—including cytokine–antibody fusions and T-cell–redirecting modalities such as bispecific T-cell engagers—are designed to localize immune activation and/or retarget immune effectors within immunologically “cold”, stroma-rich tumors. In this review, we integrate recent clinical and translational advances in ADCs and emerging IFP platforms across gastric, colorectal, pancreatobiliary and hepatocellular cancers, with particular attention to organ-dependent efficacy–toxicity trade-offs (e.g., interstitial lung disease (ILD) associated with DXd-based ADCs; cytokine release syndrome with T-cell engagers) and convergent resistance mechanisms, including antigen loss, impaired payload processing, immune exhaustion, and stromal exclusion. We further propose “immunocytotoxic convergence” as a hypothesis-generating and testable working model: under specific conditions, ADC-driven cytoreduction, immunogenic stress signatures consistent with immunogenic cell death (ICD), and/or stromal remodeling may transiently improve immune accessibility and thereby create a window for subsequent immune amplification by IFPs. Direct clinical evidence for an explicit ADC→IFP Prime–Amplify sequence in GI cancers remains limited. We therefore summarize the current evidence base, define key failure modes and safety constraints, and outline biomarker-enabled experimental and early-phase trial approaches needed to validate—or falsify—this sequencing concept.