Research

Unleashing the potential of the immune system through multipronged approaches to overcome therapeutic resistance and thwart cancer metastasis

The cells of the innate immune system, such as macrophages, neutrophils, dendritic cells, NK cells, and NKT cells, are critical in initiating and orchestrating an effective anti-tumor immune response. However, these cells are often suppressed within the tumor microenvironment or co-opted to promote tumor progression and metastasis. Our research aims to advance the development of next-generation breast cancer therapies by empowering the innate immune system. Building upon our recent discoveries, we use various strategies to harness the anti-tumor potential of innate immune cells, such as small-molecule compounds, nanomedicine-based combination therapies, and antibody-conjugated drugs. In cases where these treatments become ineffective due to drug resistance, we employ gene editing and high-throughput screening techniques to identify the key regulators that enable tumors to resist the innate immune effectors. By gaining a deeper understanding of the interplay between tumor cell-intrinsic signaling and the innate immune system, our goal is to develop combinatorial multipronged cancer therapies for advanced and metastatic breast cancers. We are also interested in expanding this line of research to include other cancer types, such as lung cancer.

Our research, among others, highlights the importance of the interaction between immunogenic, metabolic, and oncogenic pathways in cancer treatment. We hypothesize that targeting immunometabolic pathways will synergize with oncogenic pathway-targeted therapies and/or immunotherapy to treat metastatic breast cancer more effectively. To identify potential therapeutic targets, we aim to decipher signaling cascades that control the intersection of oncogenic and immunometabolic pathways in the context of drug resistance. Our research has revealed that metabolites secreted by tumor-associated macrophages (TAMs) play a crucial role in cancer progression and therapeutic resistance in triple-negative breast cancer (TNBC). We will investigate the underlying mechanisms and modulate metabolic pathways in TAMs to overcome therapeutic resistance. Our findings will likely extend to other types of cancers and various anti-cancer drugs.

We aim to engineer innate immune cells to achieve significant breakthroughs in the treatment of solid tumors. Our recent findings suggest that the gene variants associated with autoimmunity can be utilized to augment anti-tumor immunity. We apply this to engineer macrophages and NK cells. To minimize off-tumor toxicity, controllable innate immune cells are designed to express anti-tumor genes triggered by specific tumor antigen(s) or cues from the tumor microenvironment. We are also using CRISPR screens to identify new regulators that can be targeted for additional engineering, thereby further enhancing the anti-tumor activity. We will investigate the effectiveness of the engineered innate immune cells as monotherapy and in combination with other treatments, such as targeted therapy, chemotherapy, or CAR T cell therapy, in therapy-resistant solid tumor models.