Graphdiyne oxide nanosheets exert anti-lymphoma effect by killing cancer stem cells and remodeling tumor microenvironment

Inflammatory and immunosuppressive tumor microenvironment (TME) is responsible for accelerating lymphoma initiation and progression. Graphdiyne oxide (GDYO) nanosheets have been shown to restrain tumor inflammation, remodel tumor microenvironment and suppress tumor growth. However, whether GDYO exerts anti-lymphoma effect has been elusive. Here, we first delineated the inflammatory and immunosuppressive signature of lymphoma TME by bioinformatic analysis. We then demonstrated the toxic effects of GDYO on multiple types of lymphoma cells in vitro. Further xenograft experiments showed that GDYO significantly eliminated tumor initiation and growth in vivo. Moreover, single-cell transcriptome sequencing of tumor tissue revealed GDYO treatment remarkably decreased the frequencies of cancer stem cells, immunosuppressive Treg cells and pro-inflammatory myeloid cells. Mechanistically, GDYO treatment markedly inhibited the Mif-Ackr3 signaling in tumor cells and CAFs, reduced expression of inflammatory cytokines in CAFs, mitigated the number of Treg cells and CSCs, which ultimately suppressed the growth of lymphoma. Finally, we showed that GDYO showed excellent biosafety and biocompatibility. Together, our study demonstrates that GDYO exerts the duplex anti-lymphoma effects by simultaneously killing the cancer stem cells and remodeling the lymphoma TME, which provide a reference for the potential application of GDYO nanomaterials as a novel nanomedicine to treat lymphoma in the future.