Nonetheless, some limits remain exist in this [9] M.E.W. Logtenberg

 X.Zhang,etal. Cancer Letters 481 (2020) 32–44 cell extract. Secondly, our data indicated that SSL6 regulates metabo- [8] P.E. Hughes, S. Caenepeel, L.C. Wu, Targeted therapy and checkpoint im- munotherapycombinationsforthetreatmentofcancer,TrendsImmunol.37(2016) lism in HCC cells. Thirdly, SSL6 sensitizes HCC to SFN by down- 462–476. regulating glycolysis. Nonetheless, some limits remain exist in this [9] M.E.W. Logtenberg, J.H.M. Jansen, M. Raaben, M. Toebes, K. Franke, study. For instant, the effects of other metabolism such as lipid meta- A.M. Brandsma, H.L. Matlung, A. Fauster, Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPalpha axis and a target for cancer immunotherapy, bolism on the SFN sensitivity also should be investigated, which may Mainten. Immune Bal. Eff. Targeted Ther. 25 (2019) 612–619. also provide new effective intervention targets. Whether SSL6 could [10] S. Kaur, S.P. Singh, A.G. Elkahloun, W. Wu, M.S. Abu-Asab, D.D. Roberts, CD47- modulateEMTviareprogramminglipidmetabolismisunknown.Dueto dependent immunomodulatory and angiogenic activities of extracellular vesicles produced by T cells, Matrix Biol. 37 (2014) 49–59. thecriticalroleofCD47intumorimmunity[9],whetherandhowSSL6 [11] X. Liu, Y. Pu, K. Cron, L. Deng, J. Kline, W.A. Frazier, H. Xu, H. Peng, Y.X. Fu, regulates the SFN sensitivity via tumor immunity await further in- M.M. Xu, CD47 blockade triggers T cell-mediated destruction of immunogenic tu- vestigation. In addition, other microbiota-derived proteins binding mors, Nat. Med. 21 (2015) 1209–1215. [12] D.R. Soto-Pantoja, S. Kaur, D.D. Roberts, CD47 signaling pathways controlling CD47orotherimmunecheckpointsshouldbeofinteresttobeexplored. cellular differentiation and responses to stress, Crit. Rev. Biochem. Mol. Biol. 50 Moreimportantly,ifonewouldliketoapplySSL6intheclinicalsetting, (2015) 212–230. several aspects should be considered, including the stage of tumor, the [13] J. Lo, E.Y. Lau, R.H. Ching, B.Y. Cheng, M.K. Ma, I.O. Ng, T.K. Lee, Nuclear factor kappa B-mediated CD47 up-regulation promotes sorafenib resistance and its long-term side effect, the immune response and existing health condi- blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice, tion of the patients,etc. Hepatology 62 (2015) 534–545. In summary, overcoming the low sensitivity and high resistance of [14] Y.Huang,Y.Ma,P.Gao,Z.Yao,TargetingCD47:theachievementsandconcernsof HCCcellstoSFNisvitalforimprovingtheefficacyoftargetedtherapy. current studies on cancer immunotherapy, J. Thorac. Dis. 9 (2017) E168–e174. [15] G.H.Y. Lin, V. Chai, V. Lee, K. Dodge, T. Truong, M. Wong, L.D. Johnson, This study elucidated the molecular mechanism of a bacteria-derived E.Linderoth,X.Pang,J.Winston,P.S.Petrova,R.A.Uger,TTI-621(SIRPalphaFc),a protein–SSL6 enhancing SFN sensitivity of HCC cells by inhibiting CD47-blockingcancerimmunotherapeutic,triggersphagocytosisoflymphomacells glycolysisvia blocking CD47 signaling. Our findings provided the mo- by multiple polarized macrophage subsets, PloS One 12 (2017) e0187262. [16] E. Elinav, W.S. Garrett, G. Trinchieri, The cancer microbiome, Nat. Rev. Canc. 19 lecular basis for the use of SSL6 as a microbiota-derived protein that (2019) 371–376. may improve the clinical therapeutic practice of HCC. [17] R.F. Schwabe, C. Jobin, The microbiome and cancer, Nat. Rev. Canc. 13 (2013) 800–812. [18] C.M. Whisner, C. Athena Aktipis, The role of the microbiome in cancer initiation Author contributions and progression: how microbes and cancer cells utilize excess energy and promote one another\'s growth, Curr Nutr Rep 8 (2019) 42–51. 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