KAIST In Situ CAR-Macrophage Therapy

The KAIST team has introduced a highly innovative form of cancer immunotherapy that turns the body’s own macrophages into potent, targeted cancer killers directly inside solid tumours. Instead of the classic, laborious route of extracting immune cells from a patient, engineering them in a lab, expanding them, and reinfusing them, this approach reprograms macrophages already present in and around the tumour microenvironment, essentially converting an abundant but usually immunosuppressed cell population into an active therapeutic agent. Solid tumours such as gastric, lung, and liver cancers typically create a dense, hostile microenvironment that physically and biochemically blocks effective immune infiltration, yet tumour-associated macrophages are plentiful within these lesions; the KAIST strategy exploits this fact by “awakening” these cells on site rather than importing external fighters.

This KAIST in situ CAR-macrophage therapy holds particular promise for advanced prostate cancer, where dense stromal barriers and immunosuppressive microenvironments often limit T cell infiltration and efficacy of checkpoint inhibitors. Prostate tumours exhibit high macrophage infiltration, making them ideal candidates for this reprogramming approach that awakens these cells to phagocytose cancer cells and remodel the tumour microenvironment toward an inflammatory state. Combined with androgen deprivation therapy (which already alters immune dynamics) the therapy could enhance antigen presentation and T cell priming, potentially improving outcomes in metastatic castration-resistant disease where current immunotherapies have shown limited success.
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The core of the technology is a sophisticated lipid nanoparticle formulation loaded with two functional cargos: an mRNA that encodes a chimeric antigen receptor (CAR) specific for a tumour-associated antigen, and an immunostimulatory agent that activates key innate immune pathways. When these nanoparticles are injected directly into the tumour, they are preferentially taken up by local macrophages, which then translate the delivered mRNA into CAR proteins on their surface while simultaneously engaging inflammatory signalling driven by the co-delivered agonist, often involving the STING (stimulator of interferon genes) pathway. The result is a population of in situ engineered CAR-macrophages capable of recognizing and engulfing cancer cells, secreting pro-inflammatory cytokines, and presenting antigens to T cells in a way that amplifies both innate and adaptive immunity. This dual-axis design, tumour antigen recognition plus strong innate activation, addresses two central barriers in the solid tumour setting: the difficulty of getting enough engineered cells into the tumour, and the tendency of the tumour microenvironment to suppress antitumour immunity.
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In preclinical melanoma models, this in-body conversion platform delivered compelling efficacy signals, significantly slowing tumour growth compared with controls and generating an immune response that did not remain confined to the single injected lesion. The treated animals showed evidence of systemic immune activation, suggesting that antigens released from dying tumour cells and presented by reprogrammed macrophages help prime T cells that can circulate and attack distant disease sites, a critical feature for tackling metastatic cancer. Importantly, because the therapy uses macrophages that are already resident within the tumour, it avoids the common delivery inefficiencies seen when engineered cells are administered intravenously and must then traffic, extravasate, and penetrate through fibrotic stroma and elevated interstitial pressure. The macrophage reprogramming also remodels the broader tumour microenvironment creating conditions that are more favourable for subsequent T cell–mediated control and for combinations with checkpoint blockade.
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Beyond efficacy, the KAIST platform directly addresses the manufacturing and scalability challenges that plague ex vivo cell therapies. Traditional CAR-T and CAR-macrophage products require patient-specific cell collection, sterile culture facilities, viral or non-viral gene transfer, quality control testing, and complex logistics, leading to treatment delays and extremely high per-patient costs. By contrast, the in situ CAR-macrophage approach can be produced as a standardizable nanoparticle drug product, theoretically manufactured at scale, stored, and administered in a much more conventional oncology workflow, greatly lowering barriers to access. The mRNA-LNP backbone is also inherently modular: changing the antigen target involves altering only the mRNA sequence, while keeping the delivery scaffold and immunostimulant architecture largely intact, which should accelerate adaptation to different tumour antigens or emerging resistance patterns. This makes the platform conceptually similar to mRNA vaccines, where the delivery vehicle remains constant while the encoded sequence is tuned to each indication, and leverages a rapidly maturing regulatory and manufacturing ecosystem around mRNA–LNP technologies.
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