Immune mechanisms in the pathogenesis of endometriosis: a comprehensive analysis of the role of NK cells, cytokines, and extracellular vesicles/exosomes

Ulrika Ottander, Emma Björk, Pernilla Israelsson, Lucia Mincheva‐Nilsson
In: Frontiers in Immunology · 2026 · vol. 17 · doi:10.3389/fimmu.2026.1885409 · W7172377827
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This review examines how impaired NK cell cytotoxicity, dysregulated cytokines, and lesion-derived extracellular vesicles create an immune-privileged environment that promotes endometriosis progression.

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Abstract

Introduction Endometriosis is a chronic, estrogen-dependent inflammatory disorder affecting approximately 10% of women of reproductive age. Retrograde menstruation is widely accepted as a primary mechanism for ectopic endometrial seeding; however, only a subset of individuals develop the disease. This suggests additional pathogenic processes. Increasing evidence suggests impaired immune surveillance as a central factor enabling ectopic endometrial tissue to persist and expand. This review aims to explore immune-associated pathogenic mechanisms in endometriosis, focusing on the interplay between natural killer (NK) cells, cytokines, and extracellular vesicles (EVs). Methods This study was conducted as a narrative review. Relevant PubMed studies addressing immune dysfunction in endometriosis were identified, with emphasis on the role of NK cells, cytokines, EVs, and EV-mediated signaling. All material chosen for referral in the review consists of published reports that were critically evaluated and discussed. Results Endometriosis is associated with impaired immune surveillance, characterized by reduced NK-cell cytotoxicity, driven by altered receptor expression and a shift toward regulatory NK-cell subsets. A dysregulated cytokine milieu combines pro-inflammatory signals that promote lesion growth with immunosuppressive factors that inhibit immune clearance of ectopic tissue. Lesion-derived EVs further contribute the lesions’ survival by suppressing cytotoxic immune function, inducing apoptosis of activated immune cells and promoting inflammation and angiogenesis. The referred results highlight key immunological mechanisms underlying endometriosis. Discussion This review presents an immune-based model in which NK-cell dysfunction, cytokine imbalance, and EV-mediated signaling cooperate to establish an immune-privileged microenvironment that promotes the survival and growth of ectopic endometrial tissue. The immune escape mechanism, described here, highlights potential targets as candidates to be tested for immunomodulatory therapies. We conclude that endometriosis should be considered a disorder fundamentally linked to mechanisms of immune dysregulation.
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Immunol. 17:1885409. doi: 10.3389/fimmu.2026.1885409) /Title (Immune mechanisms in the pathogenesis of endometriosis: a comprehensive analysis of the role of NK cells, cytokines, and extracellular vesicles/exosomes) >> endobj 3 0 obj <> stream application/pdf Ulrika Ottander Emma Björk Pernilla Israelsson Lucia Mincheva-Nilsson Ottander U, Björk E, Israelsson P and Mincheva-Nilsson L (2026) Immune mechanisms in the pathogenesis of endometriosis: a comprehensive analysis of the role of NK cells, cytokines, and extracellular vesicles/exosomes. Front. Immunol. 17:1885409. doi: 10.3389/fimmu.2026.1885409 Copyright © 2026 Ottander, Björk, Israelsson and Mincheva-Nilsson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. endometriosis immune surveillance NK cells NKG2D MICA/B FasL cytokines EVs/exosomes Immune mechanisms in the pathogenesis of endometriosis: a comprehensive analysis of the role of NK cells, cytokines, and extracellular vesicles/exosomes endometriosis; immune surveillance; NK cells; NKG2D; MICA/B; FasL; cytokines; EVs/exosomes 2026-08-02T13:16:12+08:00 2026-08-02T13:16:19+08:00 2026-08-02T13:16:19+08:00 True https://www.frontiersin.org/legal/copyright-statement uuid:22f3f701-2421-47fc-b37d-d275b1e2c7bc uuid:f64d3e46-7e4c-4527-a2d9-ade52cccb121 endstream endobj 4 0 obj <> endobj 5 0 obj <> endobj 6 0 obj <> endobj 7 0 obj <> endobj 8 0 obj <> endobj 9 0 obj [ 18 0 R ] endobj 10 0 obj <> endobj 11 0 obj <> endobj 12 0 obj <> endobj 13 0 obj <> endobj 14 0 obj <> endobj 15 0 obj << /A 43 0 R /Alt (Diagram illustrating the immunological interactions in endometriotic lesions, showing cytokine-induced inflammation, immune cell apoptosis, immune suppressive exosomes, NK cell functional impairment, and overall immune suppression and immune privilege within endometriosis pathophysiology.) /K 0 /P 8 0 R /Pg 36 0 R /S /Figure /T () >> endobj 16 0 obj << /A 44 0 R /Alt (Illustration titled \215The landscape of endometriosis\216 featuring two mountain shapes representing the processes of local inflammation and immune escape, with immune suppression described in the valley. Four text boxes explain key aspects: inflammatory response \(driven by cytokines, exosomal miRNA, and lncRNA\), survival and protection of endometriotic lesions \(via immunosuppressive factors\), failure to clear endometrial tissue \(due to impaired receptor and immune function\), and clinical implications \(dysmenorrhea, chronic pelvic pain, infertility, and potential malignant transformation\).) /K 1 /P 8 0 R /Pg 36 0 R /S /Figure /T () >> endobj 17 0 obj <> endobj 18 0 obj << /F 46 0 R /I <> >> endobj 19 0 obj << /Limits [ ] /Names [ 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R 53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R 59 0 R 60 0 R 61 0 R 62 0 R 63 0 R 64 0 R 65 0 R 66 0 R 67 0 R 68 0 R 69 0 R 70 0 R 71 0 R 72 0 R 73 0 R 74 0 R 75 0 R 76 0 R 77 0 R 78 0 R 79 0 R 80 0 R 81 0 R 82 0 R 83 0 R 84 0 R 85 0 R 86 0 R 87 0 R 88 0 R 89 0 R 90 0 R 91 0 R 92 0 R 93 0 R 94 0 R 95 0 R 96 0 R 97 0 R 98 0 R 99 0 R 100 0 R 101 0 R 102 0 R 103 0 R 104 0 R 105 0 R 106 0 R 107 0 R 108 0 R 109 0 R 110 0 R ] >> endobj 20 0 obj << /Limits [ ] /Names [ 111 0 R 112 0 R 113 0 R 114 0 R 115 0 R 116 0 R 117 0 R 118 0 R 119 0 R 120 0 R 121 0 R 122 0 R 123 0 R 124 0 R 125 0 R 126 0 R 127 0 R 128 0 R 129 0 R 130 0 R 131 0 R 132 0 R 133 0 R 134 0 R 135 0 R 136 0 R 137 0 R 138 0 R 139 0 R 140 0 R 141 0 R 142 0 R 143 0 R 144 0 R 145 0 R 146 0 R 147 0 R 148 0 R 149 0 R 150 0 R 151 0 R 152 0 R 153 0 R 154 0 R 155 0 R 156 0 R 157 0 R 158 0 R 159 0 R 160 0 R 161 0 R 162 0 R 163 0 R 164 0 R 165 0 R 166 0 R 167 0 R 168 0 R 169 0 R 170 0 R 171 0 R 172 0 R 173 0 R 174 0 R ] >> endobj 21 0 obj << /Limits [ ] /Names [ 175 0 R 176 0 R 177 0 R 178 0 R 179 0 R 180 0 R 181 0 R 182 0 R 183 0 R 184 0 R 185 0 R 186 0 R 187 0 R 188 0 R 189 0 R 190 0 R 191 0 R 192 0 R 193 0 R 194 0 R 195 0 R 196 0 R 197 0 R 198 0 R 199 0 R 200 0 R 201 0 R 202 0 R 203 0 R 204 0 R 205 0 R 206 0 R 207 0 R 208 0 R 209 0 R 210 0 R 211 0 R 212 0 R 213 0 R 214 0 R 215 0 R 216 0 R 217 0 R 218 0 R 219 0 R 220 0 R 221 0 R 222 0 R 223 0 R 224 0 R 225 0 R 226 0 R 227 0 R 228 0 R 229 0 R 230 0 R 231 0 R 232 0 R 233 0 R 234 0 R 235 0 R 236 0 R 237 0 R 238 0 R ] >> endobj 22 0 obj << /Limits [ ] /Names [ 239 0 R 240 0 R 241 0 R 242 0 R 243 0 R 244 0 R 245 0 R 246 0 R 247 0 R 248 0 R 249 0 R 250 0 R 251 0 R 252 0 R 253 0 R 254 0 R 255 0 R 256 0 R 257 0 R 258 0 R 259 0 R 260 0 R 261 0 R 262 0 R 263 0 R 264 0 R 265 0 R 266 0 R 267 0 R 268 0 R 269 0 R 270 0 R 271 0 R 272 0 R 273 0 R 274 0 R 275 0 R 276 0 R 277 0 R 278 0 R 279 0 R 280 0 R 281 0 R 282 0 R 283 0 R 284 0 R 285 0 R 286 0 R 287 0 R 288 0 R ] >> endobj 23 0 obj << /Dest

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