Summary Immunotherapy has yielded impressive results, but only for a minority of patients with cancer. Therefore, new approaches that potentiate immunotherapy are a pressing medical need. Ferroptosis is a newly described type of programmed cell death driven by iron-dependent phospholipid peroxidation via Fenton chemistry. Here, we developed iron oxide-loaded nanovaccines (IONVs), which, chemically programmed to integrate iron catalysis, drug delivery, and tracking exploiting the characteristics of the tumor microenvironment (TME), improves immunotherapy and activation of ferroptosis. The IONVs trigger danger signals and use molecular disassembly and reversible covalent bonds for targeted antigen delivery and improved immunostimulatory capacity and catalytic iron for targeting tumor cell ferroptosis. IONV- and antibody-mediated TME modulation interfaced with imaging was important toward achieving complete eradication of aggressive and established tumors, eliciting long-lived protective antitumor immunity with no toxicities. This work establishes the feasibility of using nanoparticle iron catalytic activity as a versatile and effective feature for enhancing immunotherapy.

Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II–IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.

The efficacy of therapies is often hampered by limited tumor drug accumulation achieved through their intravenous administration, and by the lack of selectivity in targeting and killing cancer cells. Amplification of tumor redox stress and ferroptotic cell death to achieve selective killing of cancer cells using iron-containing agents has attracted considerable interest. However, these agents need high doses and multiple injection regimens and have limited success in the treatment of cancers such as melanoma. Melanoma often metastasizes via lymphatic vessels, where the metastasizing cells experience less redox stress and are protected from ferroptosis. Here it is shown that phospholipid-modified Pt(IV) prodrug-loaded iron oxide nanoparticle (IONP)-filled micelles (mIONP-PL-Pt(IV)), which integrate redox reactivity and iron-enabled catalytic therapeutic features with effective nanoparticle-assisted lymphatic delivery, provide significantly enhanced suppression of melanoma tumor growth compared to cisplatin-based chemotherapy and IONP treatments. Peroxidase-like activity, redox-triggered release of cisplatin, and reactivity with hydrogen peroxide and ascorbic acid are contributors toward the induction of a combined ferroptosis-based and cisplatin anti-melanoma treatment. Treatment with mIONP-PL-Pt(IV) provides significant tumor control using cumulative treatment doses 10-100-fold lower than reported in intravenously administered treatments. This work demonstrates the potential of enhancing chemotherapeutic and iron-based catalytic nanomedicine efficacy exploiting nanoparticle-enabled lymphatic trafficking.

Cancer immunotherapies have established their relevance in the clinic in recent years. These therapies have increased patient survival rates with few toxic side-effects. However, they still suffer from low patient response rates. With the progression of the disease, tumors become increasingly heterogeneous, which poses limits to the development of universal, “off the shelf” cures. Nanotechnology allows insight over novel therapy strategies to better suit the specificities and uniqueness of each patient’s cancer. In this work, a chemistry and material science approach enabled the development of iron oxide nanoparticle-filled nanovaccines (IONVs) to exploit the biochemical features of the tumor microenvironment for cancer immunotherapy and combination therapy. A systematic nanoparticle engineering rationale is stablished to “programme” IONVs for: (i) cancer cell sensitization to oxidative damage and ferroptosis; (ii) pH-catalysed disassembly and drug release; (iii) macrophage repolarization towards tumor-suppressing phenotypes; (iv) optimization of tumor-antigen processing and cross-presentation; (v) optimization of platinum-based prodrug delivery for chemotherapy and chemoimmunotherapy; (vi) integration of directing ligands for active targeted drug delivery; (vii) monitorable therapy biodistribution; and (viii) synergy with state-of-the-art antibody-based immunotherapies.Systematic IONV engineering provided control over distinguishable device properties such as size, charge, stability, chemical reactivity, bioactive molecule loading and particle surface functionalization. The device integrated iron catalysis for cancer-cell specific activation of ferroptosis, immunostimulatory redox stress and site-specific disassembly for targeted drug release. IONVs were visualized to accumulate into the tumor tissue as well as immune cell-rich tissues such as spleen and lymph nodes. Their high biocompatibility enabled immune cell activation for multipronged antitumor action. The results show how IONVs can unite and improve concurrently effective anticancer strategies, resulting in complete elimination of established aggressive tumors and acquisition of protective long-term immunity. Overall, this work demonstrates the suitability of programmable IONVs to act as generalizable platforms for cancer immunotherapy enhancement.