Tumor-killing nanoreactors fueled by tumor debris can enhance radiofrequency ablation therapy and boost antitumor immune responses

Zhijuan Yang,Xianwen Wang,Ziliang Dong,Liangzhu Feng,Wei Li,Zhuang Liu,Yujie Zhu,Nailin Yang

doi:10.1038/s41467-021-24604-9

Zhijuan Yang, Xianwen Wang + Show 6 more

Open Access

https://doi.org/10.1038/s41467-021-24604-9

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Abstract

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.

Highlights

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites
We prepared a type of tumor debris fueled tumorkilling nanoreactors by encapsulating both LOXs and hemin with poly(lactic-co-glycolic acid) (PLGA) via our developed CaCO3 assisted double emulsion process to work as the immunogenic adjuvant nanomedicine for both RFA treatment and ICB immunotherapy
It was found that such HLCaP NRs could effectively neutralize the acidic residual tumor mass (Supplementary Fig. 3), which may be able to reverse the immunosuppressive tumor microenvironment (TME) and benefit ICB immunotherapy according to those previous reports[14,44]

Summary

Introduction

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. In this study, by co-encapsulation of LOX and an iron catalyst (hemin) with PLGA via a CaCO3-assisted double emulsion method, we obtain a unique type of pH-responsive nanoreactors which are able to initiate continuous lipid peroxidation from the PUFA existing in tumor debris generated post RFA of tumors. By introducing sodium bicarbonate (NaHCO3) and calcium chlorides (CaCl2) to form calcium carbonate (CaCO3) inside the internal water phase of double emulsions, the obtained hemin and LOX co-loaded CaCO3-encapsulated PLGA nanoreactors (HLCaP NRs) showed higher loading efficiencies for LOX and hemin, both of which could be released in a pHresponsive manner ascribing to the pH-dependent decomposition of CaCO3 As a result, such HLCaP NRs would enable pHresponsive production of cytotoxic lipid radicals with these PUFAs existing in cancer cell lysates, thereby inducing immunogenic cell death (ICD). This work highlights the design of effective tumor debris fueled antitumor strategy to synergistically augment the therapeutic efficacy of both conventional RFA and anti-PD-l immunotherapy, to effectively eliminate primary residual tumors with direct RFA treatment and further inhibit the tumor growth at distant metastatic sites

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