Ru(II)-Photoactive Agents for Targeting ER Stress and Immunogenic Cell Death.
Madeline DenisonAlexander UllrichMackenzie K HerroonShane MeccaClaudia TurroIzabela PodgorskiHeather M GibsonJeremy J KodankoPublished in: bioRxiv : the preprint server for biology (2024)
Immunotherapy has emerged as a promising avenue for cancer treatment by bolstering the immune system's ability to recognize and attack cancer cells. Photodynamic therapy shows potential in enhancing antitumor immunity, though the mechanisms behind its success are not fully understood. In this manuscript, we investigate two previously reported green light activated PCT/PDT agents where compound 2 - [Ru(tpy)(Me2bpy)( 3 )] 2+ , (tpy = 2,2':6',2''- terpyridine, Me2bpy = 6,6'-dimethyl-2,2'-bipyridine, 3 = pyridyl-BODIPY-I2,) - shows remarkable photoselectivity in assays containing both 2D cancer cells and 3D cocultures containing BALB/c macrophages and 4T1 murine breast cancer cells. Through flow cytometry and protein analysis, we found complex 2 displays superior evidence of induced endoplasmic reticulum (ER) stress markers and indicators of immunogenic cell death (ICD) compared to its ligand 3 , despite its weaker photoselectivity. Most importantly, these results were supported by in vivo studies where 2 produced anti-tumor immunity against the 4T1 tumor model in BALB/c mice. Complete tumor elimination was achieved in 2/8 mice, and these mice were both protected against a subsequent contralateral rechallenge and showed increased ex vivo peripheral tumor antigen-specific recall, suggesting memory T cells are induced by 2 . Signatures of M1 macrophage polarization were also evident in tumor tissue from the remaining 6/8 mice treated with 2 compared to untreated tumors. These findings demonstrate Ru(II) complexation plays a critical role in ER targeting which triggers ICD, highlighting the potential of Ru(II) agents as future in situ tumor vaccines.
Keyphrases
- cell death
- photodynamic therapy
- endoplasmic reticulum
- high fat diet induced
- flow cytometry
- breast cancer cells
- type diabetes
- cancer therapy
- gene expression
- climate change
- drug delivery
- cell proliferation
- wild type
- cell cycle arrest
- high throughput
- human health
- adipose tissue
- amino acid
- signaling pathway
- single molecule
- pi k akt