A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response

Abstract

Treatment of triple-negative breast cancer (TNBC) is challenging because of its “COLD” tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B + CD8 + T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)–like endoplasmic reticulum kinase (PERK)–mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.

Insights into molecular mechanisms of chemotherapy resistance in cancer

“…Similarly, combination of celastrol, and doxorubicin has exhibited a synergistic effect by inducing sphingolipid-mediated apoptosis within colon cancer cells [96] . Additionally, combination of docetaxel and carboplatin have been shown to trigger an immunogenic cascade involving ceramide elevation, PERK-mediated apoptotic cell death, and subsequent immunogenic cell death [97] . These mechanistic insights highlight the potential of various drug combinations for precise and effective cancer therapy, opening avenues for further investigation and clinical translation.…”

“…Combination therapies targeting anti-apoptotic proteins or activating pro-apoptotic pathways along with targets in PI3K/AKT/mTOR pathway, provide opportunities to counter multiple nodes in these complex signaling circuits. Exploiting different nano-based strategies targeting sustained drug release, acidic pH of the tumor, TME, antibody conjugation, or use of ‘cocktail therapy’ for reversal of drug resistance are currently being widely studied to overcome MDR and efflux pump activation [95] , [96] , [97] , [98] . Metabolic shifts in cancer cells promoting resistance are being addressed by targeting specific metabolic pathways or combining metabolic modulators/inhibitors with standard chemo- or immuno-therapy.…”

Decoding immunogenic cell death from a dendritic cell perspective

“…Consistent with this, infection of cancer cells with Salmonella results in oxidative stress‐induced unfolded protein response (UPR), the major pathway elicited following the loss of ER homeostasis, and in the release of immunogenic peptides generated by the tumor proteasome with antitumor immunity promoting effects 145 . The mechanism underpinning the surface relocation of CRT during ICD has been shown to require the UPR sensor eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK) and its direct downstream target, the eukaryotic translation initiation factor 2 subunit alpha (eIF2α) 105,136,146,147 . PERK coordinates the ER‐to‐Golgi transport and SNARE‐mediated exocytosis of CRT to the PM, through a pathway incited by loss of ER‐Ca 2+ homeostasis and ROS 136,147 .…”

“…145 The mechanism underpinning the surface relocation of CRT during ICD has been shown to require the UPR sensor eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK) and its direct downstream target, the eukaryotic translation initiation factor 2 subunit alpha (eIF2α). 105,136,146,147 PERK coordinates the ERto-Golgi transport and SNARE-mediated exocytosis of CRT to the PM, through a pathway incited by loss of ER-Ca 2+ homeostasis and ROS. 136,147 Why PERK among the members of the UPR provides the dominant signal for the relocation of CRT to the PM, is still unclear.…”