Gut microbial diversity is preserved through localised chemo-immunotherapy delivery in a KPC mouse model of pancreatic cancer

Systemic chemotherapy and immunotherapy can disrupt gut microbial homeostasis, contributing to inflammation, treatment-related toxicity, and diminished anti-tumour immunity in pancreatic ductal adenocarcinoma (PDAC). Here, we evaluated whether localised delivery of chemo-immunotherapy via biodegradable implants could mitigate these adverse effects and preserve gut microbiota integrity. Using a syngeneic KPC mouse model of PDAC, we compared systemic versus implant-based delivery of gemcitabine/nab-paclitaxel and anti-CD40/anti-PD1 antibodies. 16S rRNA sequencing of faecal samples revealed that systemic chemo-immunotherapy significantly reduced alpha diversity, depleted immunoregulatory species (e.g. Akkermansia muciniphila, Bifidobacterium longum), and enriched pathobionts (Escherichia coli, Clostridium septicum), accompanied by elevated intestinal pro-inflammatory cytokines. In contrast, localised delivery preserved microbial diversity, maintained beneficial taxa and suppressed inflammatory cytokine levels. Further, high-dose localised chemotherapy promoted M1 macrophage polarisation while preserving microbiota more effectively than even low-dose systemic regimens. This is the first study to demonstrate that spatial control of drug exposure via localised delivery can protect the gut microbiome and modulate systemic immunity in PDAC. These findings subsequently provide proof-of-concept that implant-based approaches can enhance tolerability and efficacy of chemo-immunotherapy by minimising microbiome disruption.