Cancer immunotherapy including adoptive T cell
therapy (ACT) is widely used in the clinic and is highly beneficial for patients with
hematological malignancies; however, it remains a challenge to develop effective
immunotherapy strategies for the treatment of solid
cancers, due to the inefficiency of the immune response and the immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) converts dying
cancer cells into a therapeutic
vaccine and stimulate a systemic
antigen-specific antitumor immune response, which can effectively subvert the immunosuppressive TME and enhance the efficiency of immune responses, relative to conventional immunotherapeutic regimens. However, the application of traditional inducers of ICD in anti-
cancer immunotherapy has been limited because of low levels of ICD induction and a lack of
tumor-targeting accumulation. Mitochondria are important for
tumor-targeting strategies and have emerged as organelles with key roles in the immune system. We hypothesized that the alteration of mitochondria in
cancer cells could be an important target for the development of an efficient ICD inducer for use in
cancer immunotherapy. Here, we report the evaluation of a mitochondria-targeted small molecule,
IR-780, that acts as an ICD inducer and exhibits exceptional
antineoplastic activity.
IR-780 specifically accumulated in
tumor cells to elicit ICD in vitro and in vivo, effectively suppressed
tumor growth and lung
metastasis, and enhanced adoptive T-cell
therapy effects against solid
tumors in mouse models. These anticancer effects were linked to dendritic cell maturation and synergistic effector T cell priming and infiltration into
tumors. The underlying mechanism involves the direct targeting of the mitochondria by
IR-780, to destroy
cancer cells, including drug-resistant
cancer cells, leading to the full exposure of
tumor-associated
antigens (TAAs), thereby enhancing
antigen-specific antitumor immune responses. These features of
IR-780 suggest that it has the advantage of leading to complete TAA exposure and the stimulation of efficient antitumor immune responses in the TME.
IR-780 has potential for use as a preparative ICD inducer, in combination with conventional immunostimulatory regimens for
cancer immunotherapy, particularly in the context of solid
tumor treatment.