1. Explore the potential of CAR-NKT cell therapy in pancreatic cancer and other solid tumors

We previously established the world's first mouse CAR-NKT platform and demonstrated that CAR-NKTs showed superior in vivo antitumor activity through the activation of CD1d-dependent immune responses in the tumor microenvironment. In the future, we will expand our studies to test the potential of CAR-NKT cell therapy in some orthotopic models like pancreatic cancer via mouse NKT platform, human NKT platform, single-RNA sequencing, and gene screen strategy.

2. Develop and refine new strategies to enhance CAR-T cell persistence, improving the effectiveness of CAR-T therapy in solid tumors

CAR-T cell costimulation provided by either CD28 or 4-1BB endodomains plays a fundamental role in promoting CAR-T cell therapeutic effects. CD28 co-stimulation mediates rapid tumor-killing of CAR-T cells, while 4-1BB causes relatively slow antitumor effects. However, 4-1BB costimulation of CAR-T cells has also been associated with better T cell persistence, metabolic fitness, and memory formation compared to CD28-costimulated CAR-T cells. In the future, we will deeply explore the signaling difference between CD28 and 4-1BB co-stimulators to modify and develop new strategies to promote CAR-T persistence to enhance current CAR-T therapy.

3. Enhancing the antitumor ability of CAR-Ts via overcoming the immune suppressive microenvironment

One of the greatest obstacles to CAR-T therapy in solid tumors is immunosuppressive TME. Among the various types of immunosuppressive cells in the TME, TAMs (specifically M2-like macrophages) are particularly abundant and their accumulation in tumors correlates with poor prognosis. In the future, we will focus on how to arm CAR-T cells targeting M2 macrophages to enhance their anti-tumor effect in solid tumors.