{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T06:00:12Z","timestamp":1785218412791,"version":"3.55.0"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chimeric antigen receptor-engineered natural killer (CAR-NK) cells have emerged as a promising off-the-shelf platform for cancer immunotherapy, with a favorable safety profile in early clinical trials and potent antitumor activity demonstrated in relapsed\/refractory (R\/R) hematologic malignancies. However, their clinical efficacy in solid tumors remains severely limited by interconnected resistance mechanisms. In this review, we systematically dissect the pathological basis of CAR-NK therapy failure in solid tumors and propose an integrative cascade resistance framework that delineates three core bottlenecks: tumor microenvironment (TME)-mediated functional exhaustion, structural defects of non-natural killer (NK)-cell-adapted chimeric antigen receptors (CARs), and trogocytosis-driven immune escape. We further characterize the context-dependent regulatory roles of the natural killer group 2 member A\u2013human leukocyte antigen E (NKG2A-HLA-E) immune checkpoint axis and the intercellular adhesion molecule 1\/lymphocyte function-associated antigen 1 (ICAM-1\/LFA-1) adhesion pathway within this cascade model, with clear stratification of evidence strength across all mechanistic conclusions. Centered on the activating-inhibitory dual-module CAR (aCAR-iCAR) system, we summarize its design principles, preclinical validation status, and potential to mitigate cascade resistance, with explicit distinction between killer cell immunoglobulin-like receptor (KIR)-based (Level 1 evidence) and NKG2A-based (Level 2\u20133 evidence) inhibitory CAR backbones. We then outline an end-to-end artificial intelligence (AI)-driven rational design framework covering target screening, structural optimization, and signaling balance calibration, and introduce the AI-nanosymbiont concept as an exogenous synergistic strategy to address TME delivery barriers. Building on the molecular heterogeneity of solid tumors, we propose a four-subtype precision stratification framework to match tumor features with tailored therapeutic regimens, and summarize core translational challenges including manufacturing constraints, regulatory gaps, and safety considerations. Overall, this review provides a balanced, evidence-graded theoretical framework for next-generation CAR-NK development against solid tumors, and generates testable hypotheses for future mechanistic and clinical investigations.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1863734","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:35:30Z","timestamp":1785216930000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual-module aCAR-iCAR NK cells for solid tumors: cascade resistance mechanisms, AI-driven engineering, and precision stratification"],"prefix":"10.3389","volume":"17","author":[{"given":"Chenru","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Gansu Provincial People\u2019s Hospital","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafei","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Gansu Provincial People\u2019s Hospital","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songchen","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Gansu Provincial People\u2019s Hospital","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Gansu Provincial People\u2019s Hospital","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Gansu Provincial People\u2019s Hospital","place":["Lanzhou, Gansu, 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