Researchers from the University of Notre Dame and Stanford University have developed a new approach for cancer immunotherapy that promises to improve efficacy and reduce systemic immune activation toxicity. The study, published in Nature Chemical Biology, uses Tumor Immune Cell Targeting Chimeras (TICTACs) to target solid tumors and increase their susceptibility to treatment while sparing healthy tissue from harm.
The advent of immunotherapy has transformed the world of cancer treatment by offering a more targeted approach to preventing, controlling, and eliminating cancer cells. In contrast to chemotherapy, which destroys both cancer and healthy cells, immunotherapy utilizes the body’s own immune system to selectively attack cancer cells. Cancers that present with solid tumors, though, are particularly difficult to target because of their high concentration of tumor-associated macrophages (TAMs), which drive resistance to therapy. TAMs carry inhibitory checkpoint receptors that signal the immune system not to attack the cells, and while methods to eliminate these inhibitors exist, they work broadly, frequently requiring limited dosing to prevent immune-related toxicity.
This study, led by Mariko Morimoto, Huisking Foundation, Inc. Assistant Professor, targeted CD206, a receptor enriched on TAMs that is associated with poor outcomes in multiple cancers. CD206 recycles materials between the cell surface and interior, making it an ideal target for shuttling compounds across the cell. The group designed a series of defined, non-polymeric glycan ligands for selective targeting and uptake of CD206. These ligands were then conjugated to antibodies against the proteins of interest to create chimeras capable of targeted degradation of TAMs. These antibody conjugates, termed Tumor Immune Cell Targeting Chimeras (TICTACs), effectively and selectively degraded the desired immune checkpoint proteins on the tumor cells, thus clearing a path for the targeted application of immunotherapy agents.
Testing their TICTACs on Raji lymphoma cells in vitro, the group found that tumor burden and metastasis were significantly reduced when used in combination with rituximab without the need for a blocking antibody. Their studies also addressed the concern that use of TICTACs would impair CD206 functioning in healthy cells. Since CD206 recycles roughly every 5 minutes with only ~20% present on the cell surface at any given time, functional depletion is unlikely. Additionally, by exploiting the natural CD206 cycle, less side effects are expected, which aligns with their experiments which showed no observable adverse effects.
Utilizing a B cell lymphoma mouse model, TICTACs also showed significantly improved efficacy in vivo when compared to treatment with rituximab alone, resulting in reduced tumor burden and lung metastasis. “We are excited about the translational implications for TICTACs based on our in vivo data,” says postdoctoral researcher Ell Handy, a co-author on the paper. “We are continuing to explore the utility of leveraging immune cells’ innate functionality as we work towards building improved, holistic immunotherapy solutions for cancer and other pressing immune disorders.”
Because the TICTACs were able to selectively remove a chosen tumor surface protein without altering the genome, this method could enable a general, non-genetic strategy for immune-cell-specific therapeutic modulation.
Professor Morimoto is the Huisking Foundation, Inc. Assistant Professor in the Department of Chemistry & Biochemistry and is an affiliated faculty member of the Harper Cancer Research Institute and the Berthiaume Institute for Precision Health. Her research has been commended with the Recognition Prize for the Marie Sklodowska Curie Award, the Herbert Wertheim UF Scripps Institute Women in Chemistry Future Leader Award, and an Amgen Award.
Morimoto, M., Roberts, D.S., Wen, R.M., Handy, E., Peterson, E.E., Stepek, G.M., Till, N.A., Brooks, J.D. and Bertozzi, C.R. “Tumor immune cell targeting chimeras reprogram tumor-associated macrophages” Nature Chemical Biology (2026). https://doi.org/10.1038/s41589-026-02258-2