Th17-to-Th1 Plasticity Under CTLA-4 Blockade: A Double-Edged Sword in Tumor Immunity and Mucosal Defense

Arif Hakan ÖNDERMehmet Mutlu Çatlı^*Kübra DEMİR ÖNDER

• Antalya Training and Research Hospital, Antalya, Türkiye

Immune checkpoint blockade targeting CTLA-4 has reshaped cancer therapy by enhancing T cell–mediated antitumor responses, yet its use is limited by mucosal immune-related adverse events (irAEs). We propose that anti-CTLA-4 therapy induces peripheral expansion of Th17 cells followed by IL-12–driven conversion into Th1-like effectors (Th17→Th1 plasticity). This dual process potentiates antitumor immunity via increased IFN-γ production and CD8⁺ T cell activation, while paradoxically depleting IL-17/IL-22–producing cells critical for mucosal barrier integrity. As a result, patients experience heightened risks of colitis, mucositis, pneumonitis, and opportunistic infections, particularly in tumors with high microbial burden (e.g., colorectal, pancreatic). Drawing on translational literature and murine models, we outline a mechanistic framework linking Th17-to-Th1 reprogramming to barrier dysfunction and irAE development. To validate this hypothesis, we recommend integrative studies combining longitudinal flow cytometric profiling of Th17/Th1 subsets, paired mucosal biopsies, and metagenomic microbiome analysis. Finally, we discuss stratified management strategies—including targeted antimicrobial prophylaxis, real-time immunophenotyping, and microbiota-based risk prediction—to mitigate toxicity without compromising efficacy. A deeper understanding of CTLA-4–driven T helper plasticity and host–microbe interactions will inform precision immunotherapy, balancing antitumor benefit against mucosal safety.