Reprogramming The Defenders: Macrophage-based Cell Therapies, Day 62

In Episode 12 (https://www.linkedin.com/posts/activity-7376495674135089152-xYFI?utm_source=share&utm_medium=member_desktop&rcm=ACoAAC7R33oBU_8RoYPHRDoVcF5C0OEYKzEXkxY), we looked into macrophages. 

𝗶𝗣𝗦𝗖‐𝗗𝗲𝗿𝗶𝘃𝗲𝗱 𝗠𝗮𝗰𝗿𝗼𝗽𝗵𝗮𝗴𝗲𝘀 
Nico Lachmann’s group has shown that iPSC (induced pluripotent stem cell)-derived macrophages can be engineered and polarized, offering a scalable, renewable source for cell therapy. [1] 

𝗖𝗔𝗥-𝗠𝗮𝗰𝗿𝗼𝗽𝗵𝗮𝗴𝗲𝘀 (𝗖𝗔𝗥‐𝗠) 
CAR‑M therapies engineer macrophages with chimeric antigen receptors, combining antigen specificity with macrophages’ innate abilities. They can: 
• directly phagocytose tumor cells, 
• secrete inflammatory cytokines (e.g., TNF, IL-12) 
• modulate TME 
• present tumor antigens to T cells, bridging innate and adaptive immunity [2][3] 

𝗖𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝗮𝗻𝗱 𝗽𝗿𝗲𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝗱𝗮𝘁𝗮 𝘀𝘂𝗽𝗽𝗼𝗿𝘁 𝘁𝗵𝗶𝘀 𝗽𝗼𝘁𝗲𝗻𝘁𝗶𝗮𝗹: 
Clinical: mesothelin-targeted CAR-M was infused into ovarian cancer patients, and showed a favorable safety profile. [4] 
Preclinical: M1 polarization of CAR-Ms further increases phagocytic and tumor-killing activity in solid tumor models. [5] 
PSMA-targeted CAR-Ms in prostate cancer were shown to undergo metabolic reprogramming (increased glycolysis), boosting their pro-inflammatory, tumoricidal phenotype. [6] 

𝗦𝘁𝗿𝗲𝗻𝗴𝘁𝗵𝘀 𝗮𝗻𝗱 𝗖𝗵𝗮𝗹𝗹𝗲𝗻𝗴𝗲𝘀: 𝘊𝘈𝘙‐𝘛 𝘷𝘴 𝘕𝘒‐𝘊𝘈𝘙 𝘷𝘴 𝘊𝘈𝘙‐𝘔 
Modality – Strengths – Challenges 
CAR‑T cells – High expansion, potent cytotoxicity – Poor solid tumor infiltration, CRS, TME suppression 
CAR‑NK cells – Less risk of GvHD, innate cytotoxicity, good safety profile Persistence and expansion in vivo – limited antigen specificity 
CAR‑Macrophages – Excellent infiltration into solid tumors; phagocytosis; TME remodeling – Limited proliferation; lower persistence; manufacturing 

𝗦𝗽𝗲𝗰𝘂𝗹𝗮𝘁𝗶𝘃𝗲 𝗛𝘆𝗽𝗼𝘁𝗵𝗲𝘀𝗶𝘀 
Future CAR‐Ms could be programmed to overexpress IL‑12 or in the TME, or carry inducible switches (such as suicide genes or small‑molecule on/off systems like TM in UniCAR) to limit systemic inflammation. 

𝗤𝘂𝗲𝘀𝘁𝗶𝗼𝗻 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗔𝘂𝗱𝗶𝗲𝗻𝗰𝗲  Which engineering feature on macrophages (e.g., switchable CAR) would you prioritize? 

Stay tuned for 𝗗𝗮𝘆 𝟲𝟯: 𝗧𝗵𝗲 𝗧𝘂𝗺𝗼𝘂𝗿 𝗠𝗶𝗰𝗿𝗼𝗲𝗻𝘃𝗶𝗿𝗼𝗻𝗺𝗲𝗻𝘁 – 𝗟𝗮𝘆𝗲𝗿𝘀 𝗼𝗳 𝗜𝗺𝗺𝘂𝗻𝗼𝘀𝘂𝗽𝗽𝗿𝗲𝘀𝘀𝗶𝗼𝗻 𝗮𝗻𝗱 𝗥𝗲𝘀𝗶𝘀𝘁𝗮𝗻𝗰𝗲

𝗥𝗲𝗳𝗲𝗿𝗲𝗻𝗰𝗲𝘀: 
1. DOI: 10.1016/j.regen.2022.100061 
2. DOI: 10.1038/s41587-020-0462-y 
3. DOI: 10.3389/fimmu.2021.783305 
4. doi: 10.1186/s13045-024-01635-5 
5. DOI: 10.1186/s12967-023-04061-2 
6. doi.org/10.1186/s13045-025-01743-w 
7. doi: 10.3389/fcell.2024.1464218 

#100Daysofimmunology #Immunology #CancerResearch #Macrophages #CAR_Macrophage #CellTherapy #SolidTumors #iPSC #InnateImmunity #TumorMicroenvironment #SyntheticImmunology