Hysteresis of IL-10R primes solid tumour microenvironment for bacterial immunotherapy

Hysteresis, a ubiquitous phenomenon in nonlinear systems, plays a vital role in diverse scientific disciplines. Here, we demonstrated the presence of hysteresis in the expression of interleukin-10 receptor (IL-10R) within the tumour microenvironment (TME) during bacterial immunotherapy. The engineered Salmonella enterica, administered intravenously, exhibited remarkable efficacy in multiple tumour types, effectively eliminating tumours and preventing recurrence and metastasis. We found that the hysteretic response of IL-10R can prime TME for bacterial homing and reinvigorate intratumoural CD8+ T cells. Furthermore, the differential IL-10R levels observed in different human tumour types suggest a potential correlation with clinical outcomes. Overall, our study not only uncovers the central role of hysteresis in driving the therapeutic effects of bacterial immunotherapy, but also provides a framework for intratumoural immunomodulation in solid tumour treatment. Overall design: The intratumoural CD8+ T cells were sorted from B16 melanoma-bearing mice after treatment with PBS or DB1, followed by total RNA extraction and bulk RNA-seq.