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Biomimetic manganese-eumelanin nanocomposites for combined hyperthermia-immunotherapy against prostate cancer.

ABSTRACT: Pro-tumoral and immunosuppressive M2-like tumor-associated macrophages (TAMs) contribute to tumor progression, recurrence and distal metastasis. However, current TAMs-modulating therapeutic strategies often encounter challenges including insufficient immune activation, weak antigen presentation ability and unsatisfactory antitumor immune performance. Herein, cyclic RGD peptide functionalized and manganese doped eumelanin-like nanocomposites (RMnMels) are reported for combined hyperthermia-immunotherapy against PC3 prostate cancer. The RMnMels could promote M2-to-M1 macrophage repolarization via scavenging multiple reactive oxygen species and remodeling the immunosuppressive tumor microenvironment. Following near-infrared light irradiation, RMnMels-mediated thermal ablation not only could destroy tumor cells directly, but also elicit the release of damage associated molecular patterns and tumor-associated antigens, provoking robust tumor immunogenicity and strong antitumor immune responses. The results showed that RMnMels could effectively scavenge reactive oxygen species and promote M2-to-M1 macrophage repolarization both in vitro and in vivo. Synergistically enhanced anti-tumor therapeutic efficacy was achieved following single administration of RMnMels plus single round of laser irradiation, evidenced by decreased primary tumor sizes and decreased number of distant liver metastatic nodules. The as-developed RMnMels may represent a simple and high-performance therapeutic nanoplatform for immunomodulation and enhanced antitumor immune responses.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8785565 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pancreatic cancer (PC) has the highest mortality rate amongst all other cancers in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of 8% for all stages of PC combined. The Whipple procedure, or pancreaticoduodenectomy, can increase survival for patients with resectable PC, however, less than 20% of patients are candidates for surgery at time of presentation. Most of the patients are diagnosed with advanced PC, often with regional and distant metastasis. In these advanced cases, chemotherapy and radiation have shown limited tumor control, and PC continues to be refractory to treatment and results in a poor survival outcome. In recent years, there has been intensive research on checkpoint inhibitor immunotherapy for PC, however, PC is characterized with dense stromal tissue and a tumor microenvironment (TME) that is highly immunosuppressive, which makes immunotherapy less effective. Interestingly, when immunotherapy is combined with radiation therapy (RT) and loco-regional hyperthermia (HT), it has demonstrated enhanced tumor responses. HT improves tumor killing via a variety of mechanisms, targeting both the tumor and the TME. Targeted HT raises the temperature of the tumor and surrounding tissues to 42?43 °C and makes the tumor more immunoresponsive. HT can also modulate the immune system of the TME by inducing and synthesizing heat shock proteins (HSP), which also activate an anti-tumor response. It is well known that HT can enhance RT-induced DNA damage in cancer cells and simultaneously help to oxygenate hypoxic regions. Thus, it is envisaged that combined HT and RT might have immunomodulatory effects in the PC-TME, making PC more responsive to immunotherapies. Moreover, the combined tripartite approach of immunotherapy, RT, and HT could reduce the overall toxicity associated with each individual therapy, while concomitantly enhancing the immunotherapeutic effect of overall individual therapies to treat local and metastatic PC. Thus, the use of a tripartite combinatorial approach could be promising and more efficacious than monotherapy or dual therapy to treat and increase the survival of the PC patients.

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Biomimetic manganese-eumelanin nanocomposites for combined hyperthermia-immunotherapy against prostate cancer.

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