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The role of the complement system in affecting the phenotype and anti-tumor function of NK cells remains poorly understood. Using the B16F10 mouse melanoma model, we demonstrated that NK cells from C3\u2212\/\u2212 mice exhibit increased expression of activation receptors (NKG2D, NKp46, and Ly49H) and reduced inhibitory receptors (NKG2A, Ly49A, and KLRG1) and high cytotoxic activity compared to C3+\/+ mice NK cells. C3\u2212\/\u2212 mice show reduced melanoma tumor growth and metastasis in an NK cell-dependent manner compared to C3+\/+ mice. Intratumoral NK cells in C3\u2212\/\u2212 mice formed a unique phenotypic cluster characterized by higher expression of T-bet, CD69, GITR, CD62L, CCR7, and increased secretion of effector cytokines (IFN-\u03b3, TNF-\u03b1, and GM-CSF) and granzyme B expression compared to C3+\/+ mice. In C3\u2212\/\u2212 mice, NK cells from both the spleen and tumors exhibit markedly higher expression levels of C3aR and C5aR1 compared to those from wild-type mice. Activation of C3aR by C3a, leads to phosphorylation of AKT and STAT3 molecules, resulting in phenotypic changes to NK cells. Furthermore, antagonising complement anaphylatoxin receptors C3aR or C5aR1 in wild-type mice resulted in reduced tumor growth, accompanied by an increase in intratumoral effector NK cells. Together, we demonstrated that complement C3 regulates the effector and cytotoxic functions of NK cells, suggesting that targeting complement C3 and the anaphylatoxin receptor may be beneficial in controlling tumor growth in the clinic.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag157","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:07:13Z","timestamp":1783012033000},"source":"Crossref","is-referenced-by-count":1,"title":["Complement C3 deficiency increases the effector and cytotoxic functions of NK cells and suppresses tumor growth"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0391-6084","authenticated-orcid":false,"given":"Pradipta","family":"Pal","sequence":"first","affiliation":[{"name":"Biotechnology Research and Innovation Council (BRIC)-National Centre for Cell Science (NCCS) , Ganeshkhind, MH, Pune,","place":["India"]},{"name":"Department of Biotechnology, Savitribai Phule Pune University , Ganeshkhind, MH, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praneet","family":"Wahi","sequence":"additional","affiliation":[{"name":"Biotechnology Research and Innovation Council (BRIC)-National Centre for Cell Science (NCCS) , Ganeshkhind, MH, Pune,","place":["India"]},{"name":"Department of Biotechnology, Savitribai Phule Pune University , Ganeshkhind, MH, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourav","family":"Paul","sequence":"additional","affiliation":[{"name":"Biotechnology Research and Innovation Council (BRIC)-National Centre for Cell Science (NCCS) , Ganeshkhind, MH, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikrujam Thoihen","family":"Meitei","sequence":"additional","affiliation":[{"name":"Biotechnology Research and Innovation Council (BRIC)-National Centre for Cell Science (NCCS) , Ganeshkhind, MH, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Sahu","sequence":"additional","affiliation":[{"name":"Biotechnology Research and Innovation Council (BRIC)-National Centre for Cell Science (NCCS) , Ganeshkhind, MH, Pune,","place":["India"]},{"name":"Department of Biotechnology, Savitribai Phule Pune University , Ganeshkhind, MH, Pune,","place":["India"]},{"name":"Regional Centre for Biotechnology, NCR Biotech Science Cluster , Faridabad, Haryana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3799-3603","authenticated-orcid":false,"given":"Girdhari","family":"Lal","sequence":"additional","affiliation":[{"name":"Biotechnology Research and Innovation Council (BRIC)-National Centre for Cell Science (NCCS) , Ganeshkhind, MH, Pune,","place":["India"]},{"name":"Department of Biotechnology, Savitribai Phule Pune University , Ganeshkhind, MH, Pune,","place":["India"]},{"name":"Regional 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