Animesh Kar, Dolly Jain, Sandeep Kumar, Kajal Rajput, Sanjay Pal, Kajal Rana, Raunak Kar, Somesh K. Jha, Nihal Medatwal, Prabhu Srinivas Yavvari, Nishant Pandey, Devashish Mehta, Harsh Sharma, Debanjan Bhattacharya, Manas K. Pradhan, Ravi Datta Sharma, Aasheesh Srivastava, Usha Agrawal, Arnab Mukhopadhyay, Sagar Sengupta, Veena S. Patil, Avinash Bajaj, Ujjaini Dasgupta

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

  • Multidisciplinary
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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.

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