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Quest to the hostile Tumour Microenvironment, a guide to engineering your arsenal

By Giorgio Matronola

While strolling through the vascular and lymphatic system, picture yourself as a T-cell - a cell of the immune system that kills pathogen-infected cells. Suddenly you find yourself inside a leukapheresis machine and snugly placed in a test tube. Though this might initially sound a bit daunting, there is no need to fret – it is a normal procedure doctors use to filter white blood cells from a patient's bloodstream. The doctors have an intriguing proposition: they would like to send you to a lab where a cellular engineer will be "pulling bits of [you] out and putting other bits in."

With these words, UCL Professor Martin Pule vividly describes CAR T-cell therapy in the BBC documentary "War in Blood". Through this innovative therapy, scientists like Dr Pule engineer T-cells to destroy cancer cells just as they would an infected cell (1).

T-cells bear receptors on their surfaces which recognise the foreign proteins, sugars, or lipids called antigens of intruding cells. When a T-cell recognises a foreign antigen, it releases toxic factors that kill the targeted cell. So why are T-cells unable to degrade our tumours? Tumour cells are still human cells, meaning their surface antigens mostly do not appear foreign to the immune system. With CAR T-cell therapy, scientists aim to equip T-cells with a chimeric receptor capable of recognising antigens highly or exclusively expressed on tumour cells, allowing the immune system to specifically respond to them (2).

However, winning the battle against solid tumours requires additional “bits” to be engineered into a CAR T-cell’s cellular makeup. Solid tumours reside in the tumour microenvironment (TME) (Figure 1), a set of hostile conditions created by the tumours which impede the interactions between a T-cell and its antigen (3).

Figure 1: CAR T-cells travelling in the bloodstream and approaching a solid tumour in the tumour microenvironment. Created with

To begin, scientists can compromise receptors on CAR T-cells. Tumours defend themselves from the immune system by secreting factors to hijack other immune cells, turning them into TME-associated immune cells (4). Indeed, TME-associated regulatory T-cells and myeloid-derived suppressor cells (MDSCs) secrete small molecules that suppress T-cell immune functions (5). For instance, TGF-Beta is a molecule which inhibits a T-cell’s ability to proliferate by tackling genes that regulate the cell cycle and downregulating receptors for molecules which drive T-cell expansion (6,7). However, by disabling the receptors for these immunosuppressive molecules that CAR T-cells bear on their surfaces, scientists make the CAR T-cells insusceptible to them (Figure 2). CAR T-cells with modified TGF-Beta receptors are being employed in clinical trials currently taking place at UCL as part of the NexTGen international program, aiming to treat paediatric solid tumours before 2030 (8).

Next, scientists aim to provide CAR T-cells with tools of their own. Tumours and TME-associated immune cells present surface inhibitors that immunosuppress CAR T-cells by binding to target receptors on the cell surface. Among these, PDL-1 and CD-47 bind PD-1 and TSP1 respectively on CAR T-cells’ surface, inhibiting them from producing immune-activating molecules like Interleukin-2 (9,10). Thankfully, PDL-1 and CD-47 inhibiting antibodies exist, allowing scientists to swiftly equip CAR T-cells with the DNA encoding them (Figure 2). The CAR T-cells can then secrete them in the TME, bind them to their targets and neutralise their immunosuppressive activity (11,12).

To fight other possible immune-inhibiting attacks from the TME, scientists are testing the use of cytokines, molecules that regulate immune cell activity. Among these, Interleukin-12 (IL-12) is a cytokine which enhances the powers of immune cells. In mice injected with tumour cells, IL-12-expressing CAR T-cells enhanced the toxic activity of T-cells. Additionally, scientists can manipulate the CAR T-cells’ cellular mechanisms to induce the expression of IL-12 only when they are in the TME, avoiding potential toxicity elsewhere in the body (Figure 2). Indeed, too much IL-12 can stimulate T-cells to be toxic in parts of the body where it is not meant to attack (13).

Additionally, tumours and TME-associated cells secrete molecules like the vascular endothelial growth factor (VEGF) which remodel the veins in a tissue vasculature. The abnormal vein system around a tumour makes it particularly challenging for CAR T-cells to infiltrate the tumour (14). To circumvent this, scientists aim to harness chemokines, small molecules which stimulate immune cell migration. CAR T-cells with modified and stable chemokine receptors are more sensitive to chemokine concentrations in tumours, allowing them to infiltrate the tumour more effectively and are currently undergoing clinical trials. (15,16).

Figure 2: CAR T-cells with additional engineered features to survive in the immunosuppressive tumour microenvironment. Created with

Once scientists are satisfied with the CAR T-cells’ new arsenal, they will re-implant them into the patient’s blood system. Their successes and failures will be closely observed to refine strategies for future quests. As research teams worldwide explore novel ways for cells to navigate the TME, additional clinical trials will be conducted, with the hope that CAR T-cell therapy will become increasingly effective against solid tumours. In the meantime, best of luck on your quest, T-cells.



1. BBC Two - War in the Blood: A Cure for Cancer?, Nature’s toolkit [Internet]. 2019. Available from:

2. Penn Medicine - Abramson Cancer Center [Internet]. CAR T-cell Therapy | Penn Medicine. Available from: CAR T Cell Therapy | Penn Medicine

3. Henke E, Nandigama R, Ergün S. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy. Front Mol Biosci [Internet]. 2020;6. Available from:

4. Lu C, Liu Y, Ali NM, Zhang B, Cui X. The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy. Front Immunol [Internet]. 2023;13. Available from:

5. Li K, Shi H, Zhang B, Ou X, Ma Q, Chen Y, et al. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer. Signal Transduct Target Ther. 2021 Oct 7;6(1):1–25.

6. Skon CN, Lee JY, Anderson KG, Masopust D, Hogquist KA, Jameson SC. Transcriptional downregulation of S1pr1 is required for establishment of resident memory CD8+ T-cells. Nat Immunol. 2013 Dec;14(12):1285–93.

7. Straathof K. Next Generation engineered T-cells for childhood solid tumours [Internet]. UCL Cancer Symposium 2023; 2023 May 17; UCL Great Ormond Institute of Child Health. Available from:

8. Riley JL. PD-1 signaling in primary T-cells. Immunol Rev. 2009 May;229(1):114.

9. Li Z, He L, Wilson KE, Roberts DD. Thrombospondin-1 Inhibits TCR-Mediated T Lymphocyte Early Activation. J Immunol. 2001 Feb 15;166(4):2427–36.

10. Suarez ER, Chang DK, Sun J, Sui J, Freeman GJ, Signoretti S, et al. Chimeric antigen receptor T-cells secreting anti-PD-L1 antibodies more eƯectively regress renal cell carcinoma in a humanized mouse model. Oncotarget. 2016 Apr 29;7(23):34341–55.

11. Dacek MM, Kurtz KG, Wallisch P, Pierre SA, Khayat S, Bourne CM, et al. Potentiating antibodydependent killing of cancers with CAR T-cells secreting CD47-SIRPα checkpoint blocker. Blood. 2023 Apr 20;141(16):2003–15.

12. Yang Y, Yang H, Alcaina Y, Puc J, Birt A, Vedvyas Y, et al. Inducible expression of interleukin-12 augments the eƯicacy of aƯinity-tuned chimeric antigen receptors in murine solid tumor models. Nat Commun. 2023 Apr 12;14(1):2068.

13. Poggi A, Varesano S, Zocchi MR. How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive. Front Immunol [Internet]. 2018; 9. Available from:

14. Liu G, Rui W, Zheng H, Huang D, Yu F, Zhang Y, et al. CXCR2-modified CAR-T-cells have enhanced traƯicking ability that improves treatment of hepatocellular carcinoma. Eur J Immunol. 2020 May;50(5):712–24.

15. Niu T. Phase I Study of A CXCR4 Modified BCMA CAR-T in Patients With Refractory and/or Relapsed Multiple Myeloma [Internet].; 2023 Dec. Report No.: NCT04727008. Available from:


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