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. 2023 Jan 30;22:20. doi: 10.1186/s12943-023-01723-z

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© The Author(s) 2023

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 5 — Combined CAR cells therapies would improve their efficacy. A CAR-M1/CAR-NK cell combination therapy model. (a) CAR-M1 genetically modified to secrete INF-γ recognize the TAA through the CAR and phagocyte the tumor. (b) The continuous secretion of INF-γ by these CAR-M maintains them in M1 phenotype and (c) induces the recruitment of CAR-NK cells genetically modified to express CXCR. Additionally, CAR-M1 secrete IL-1, IL-12 and IL-15 which (d) induce the upregulation of CAR-NK KAR), CXCR, FASL and CD16. The upregulation of activated CAR-NK cells (e) enhanced cytotoxicity against tumor cells. Additionally, activated CAR-NK cells secrete IFN-γ and TNFα which (f) stimulate endogenous cytotoxic T cells. Moreover, (g) CXCR-expressing CAR-NK cells have a higher potential to migrate and infiltrate the CXCL secreting TME. B CAR-M1/CAR-T cell combination therapy model. (a) CAR-M1 recognize TAA with CAR and phagocyte the tumor. TAA presentation by CAR-M1 induces (b) the activation of Th1 immune responses. The interaction between CAR-M1-MHC-TAA and Th1 induces (c) IFN-γ production by Th1. (d) IFN-γ maintains CAR-M in M1 phenotype. (e) Activated CAR-M1 cells produces pro-inflammatory cytokines and chemokines, ROS and TNF-α involved in the activation of Th1 and the recruitment of CAR-T cells into the tumor site. (f) CAR-M1 are also able to produce NO which contributes with IL-1 and IL-6 to the generation of CRS. (g) IL-1Ra-expressing-genetically modified CAR-T cells inhibit the CRC mediated by IL-1 and IL-6. (h) Recruited CAR-T cells recognize TAA and induce tumor cytotoxicity. C CAR-NK/CAR-T cell combination therapy model. (a) CAR-NK cells recognize TAA by CAR and ligands expressed on tumor cells. (b) CCL-secreting CAR-NK cells recruit CAR-T cells by releasing IL-8, CCL3, and CCL5. CAR-NK expressing chemokines are better recruited to cancer cells and (c) kill them directly by apoptosis. (d) CAR-T cells secrete PD-1 blocking antibodies and inhibits this interaction with PDL-1. (e) CAR-T cells induce cancer cells killing by releasing granzyme and perforin. (f) CAR-T cell recruit CAR-NK