This Endeavor Award seeks to harness the antitumor potential of tumor-associated macrophages (TAMs), which are abundant in the tumor microenvironment but typically adopt immunosuppressive states that support cancer growth. Although appropriately programmed macrophages can directly kill cancer cells and stimulate adaptive immunity, our understanding of how their functional states are established is incomplete, limiting efforts to reprogram TAMs therapeutically.
The investigators have discovered that TAM programming occurs through a two-stage process. Tumors first alter myeloid progenitors in the bone marrow through systemic signals involving oxidative stress, ferroptosis resistance, and cytokine networks, and subsequently reinforce immunosuppressive macrophage states through local interactions within the tumor. These mechanisms appear conserved across multiple cancer types and species, suggesting that they represent fundamental features of tumor-mediated immune suppression.
The team will define the molecular programs controlling these systemic and local stages and determine whether they can be therapeutically disrupted to generate antitumor macrophages. Using human tumor profiling, in vivo functional genomics, mouse and zebrafish cancer models, and pharmacologic approaches, they will investigate how oxidative stress and ferroptosis regulate myeloid development; identify tumor-derived signals and macrophage receptors that control TAM behavior; and evaluate promising targets and therapeutic combinations in lung and skin cancer models, including their ability to enhance response to anti-PD-1 therapy.
By treating TAM programming as a multistage process rather than solely a local feature of the tumor microenvironment, this work could reveal new opportunities to rewire macrophages from drivers of immune suppression into potent anti-cancer effectors. The resulting therapeutic strategies could complement T-cell-directed immunotherapies while also providing a distinct mechanism for eliminating tumors that resist conventional immunotherapy.