The 𝘵𝘶𝘮𝘰𝘶𝘳 𝘮𝘪𝘤𝘳𝘰𝘦𝘯𝘷𝘪𝘳𝘰𝘯𝘮𝘦𝘯𝘵 (𝘛𝘔𝘌) 𝘪𝘯 𝘴𝘰𝘭𝘪𝘥 𝘤𝘢𝘯𝘤𝘦𝘳𝘴 𝘤𝘳𝘦𝘢𝘵𝘦𝘴 𝘮𝘶𝘭𝘵𝘪𝘱𝘭𝘦 𝘱𝘩𝘺𝘴𝘪𝘤𝘢𝘭, 𝘮𝘦𝘵𝘢𝘣𝘰𝘭𝘪𝘤 𝘢𝘯𝘥 𝘪𝘮𝘮𝘶𝘯𝘰𝘴𝘶𝘱𝘱𝘳𝘦𝘴𝘴𝘪𝘷𝘦 𝘣𝘢𝘳𝘳𝘪𝘦𝘳𝘴: dense stroma and extracellular matrix impede T-cell infiltration, hypoxia and nutrient deprivation limit effector persistence, and immunosuppressive cells (Tregs, MDSCs) secrete TGF-β, IL-10 and other inhibitors that reduce CAR-T activation [1][2]. 

Research groups in Germany such as 𝗙𝗿𝗮𝗻𝘇𝗶𝘀𝗸𝗮 𝗕𝗹𝗮𝗲𝘀𝗰𝗵𝗸𝗲 at DKFZ/KiTZ (Heidelberg) – working on high-throughput CRISPR screening of CAR-T cells for solid-tumour fitness [3] – and 𝗝𝘂𝗱𝗶𝘁𝗵 𝗙𝗲𝘂𝗰𝗵𝘁 at University of Tubingen – developing senolytic CAR-T designs and metabolic reprogramming strategies for solid tumours [4] are advancing next-generation solutions.  

𝗘𝘅𝗮𝗺𝗽𝗹𝗲𝘀 𝗼𝗳 𝗲𝗺𝗲𝗿𝗴𝗶𝗻𝗴 𝘀𝘁𝗿𝗮𝘁𝗲𝗴𝗶𝗲𝘀 
• 𝘌𝘯𝘨𝘪𝘯𝘦𝘦𝘳𝘪𝘯𝘨 𝘤𝘩𝘦𝘮𝘰𝘬𝘪𝘯𝘦 𝘳𝘦𝘤𝘦𝘱𝘵𝘰𝘳 𝘦𝘹𝘱𝘳𝘦𝘴𝘴𝘪𝘰𝘯 (e.g., CCR8) or dominant-negative TGF-β receptors in CAR-T cells enhances tumor recruitment and resistance to TME signalling [5]. 
• ´𝘈𝘳𝘮𝘰𝘳𝘦𝘥 𝘊𝘈𝘙-𝘛 𝘤𝘦𝘭𝘭𝘴 𝘵𝘩𝘢𝘵 𝘴𝘦𝘤𝘳𝘦𝘵𝘦 𝘐𝘓-12 or checkpoint-blocking proteins remodel the TME and promote endogenous immunity [2][6]. 
• Dual-or bispecific CARs target multiple antigens or combine tumor signal + CAR activation logic (𝘚𝘺𝘯𝘕𝘰𝘵𝘤𝘩 𝘳𝘦𝘤𝘦𝘱𝘵𝘰𝘳𝘴) to improve selectivity and reduce off-tumor toxicity [6]. 

𝗦𝗽𝗲𝗰𝘂𝗹𝗮𝘁𝗶𝘃𝗲 𝗵𝘆𝗽𝗼𝘁𝗵𝗲𝘀𝗶𝘀: A promising path for solid tumor CAR-T therapy as a three-phase approach:  
1) pre-conditioning the TME with targeted therapies or low-dose radiation to open stromal barriers 
2) infiltration-optimized CAR-T infusion engineered for resistance to TME suppression 
3) maintenance therapy with endogenous immune priming or on-demand ´booster´ CAR-T infusions  

𝗤𝘂𝗲𝘀𝘁𝗶𝗼𝗻 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗮𝘂𝗱𝗶𝗲𝗻𝗰𝗲: Which TME barrier is the most critical to overcome first in advancing CAR-T therapy for solid tumors? 

Stay tuned for 𝗗𝗮𝘆 𝟱𝟴: 𝗡𝗲𝘅𝘁-𝗚𝗲𝗻 𝗖𝗔𝗥-𝗧𝘀 – 𝗦𝘆𝗻𝘁𝗵𝗲𝘁𝗶𝗰 𝗕𝗶𝗼𝗹𝗼𝗴𝘆 𝗮𝗻𝗱 𝗣𝗿𝗲𝗰𝗶𝘀𝗶𝗼𝗻 𝗖𝗲𝗹𝗹 𝗧𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀 

𝗥𝗲𝗳𝗲𝗿𝗲𝗻𝗰𝗲𝘀: 
1. DOI: 10.1038/s41571-023-00832-4 
2. DOI: 10.1016/j.tips.2024.10.016 
3. DOI: 10.1038/s41408-021-00499-z 
4. DOI: 10.1016/j.ymthe.2020.08.011 
5. DOI: 10.1126/sciadv.abi5781 
6. DOI: 10.1007/s12026-025-09687-6 

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