Shenghong Wu, Ran Cui, Kangnan Zhao, Zhen Yang, Zihan Yi, Weiwei Cao, Li Ye
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.