The role of residue chirality of polypeptide hydrogels in regulating local immune microenvironment for anti-tumor immune responses

The impact of chirality on immune response has attracted great interest in cancer vaccine research recently. However, the study of chiral synthetic polypeptide hydrogels as cancer vaccines as well as of the impact of biomaterials itself for antitumor immunotherapy has rarely been reported. Herein, we demonstrated the key role of residue chirality of polypeptides hydrogels in antitumor immunity and local immune microenvironment regulation. Compared to poly(γ-ethyl-L-glutamate)-based hydrogels (L-Gel), poly(γ-ethyl-D-glutamate)-based hydrogels (D-Gel) induced greater immune cell infiltration. Unexpectedly, D-Gel caused higher levels of suppressive markers on antigen-presenting cells and even induced stronger T cells exhaustion than L-Gel. Finally, D-Gel established a local chronic inflamed and immunosuppressive microenvironment and showed insufficient anti-tumor effects. Conversely, the milder host immune responses induced by L-Gel led to more effective tumor inhibition. This study provides new insights on the role of residue chirality in the regulation of local immune microenvironment and affecting antitumor immune response. To further characterize the heterogeneity of the local immune microenvironment following injection with the different hydrogels, bulk RNA sequencing (RNA-seq) was performed with the Illumina sequencing platform. We then performed gene expression profiling analysis using data obtained from RNA-seq of three hydrogel tissues of each group. Comparative gene expression profiling analysis of RNA-seq data for L-Gel and D-Gel.