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Since tumor cells have evolved a series of mechanisms to escape from NK cells, developing methods for increasing the NK cell antitumor activity is of utmost importance. It is previously shown that an ex vivo stimulation of patient\u2010derived NK cells with interleukin (IL)\u20102 and Hsp70\u2010derived peptide TKD (<jats:styled-content>TKD<\/jats:styled-content>NNLLGRFELSG, aa450\u2010461) results in a significant upregulation of activating receptors including CD94 and CD69 which triggers exhausted NK cells to target and kill malignant solid tumors expressing membrane Hsp70 (mHsp70). Considering that TKD binding to an activating receptor is the initial step in the cytolytic signaling cascade of NK cells, herein this interaction is studied by molecular docking and molecular dynamics simulation computational modeling. The in silico results showed a crucial role of the heterodimeric receptor CD94\/NKG2A and CD94\/NKG2C in the TKD interaction with NK cells. Antibody blocking and CRISPR\/Cas9\u2013mediated knockout studies verified the key function of CD94 in the TKD stimulation and activation of NK cells which is characterized by an increased cytotoxic capacity against mHsp70 positive tumor cells via enhanced production and release of lytic granules and pro\u2010inflammatory cytokines.<\/jats:p>","DOI":"10.1002\/advs.202305998","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T02:56:36Z","timestamp":1706756196000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Crosstalk Between NK Cell Receptors and Tumor Membrane Hsp70\u2010Derived Peptide: A Combined Computational and Experimental Study"],"prefix":"10.1002","volume":"11","author":[{"given":"Mina","family":"Yazdi","sequence":"first","affiliation":[{"name":"Pharmaceutical Biotechnology Department of Pharmacy Ludwig\u2010Maximilians\u2010Universit\u00e4t (LMU)  81377 Munich 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