Engineering Bioinspired Nanomedicines to Mitigate the Resistance to Cancer Immunotherapy

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS:The current era has witnessed the success of immunotherapy, in particular, immune checkpoint blockade (ICB) therapy, at an unprecedented pace. However, immunotherapy often fails to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex tumor microenvironment (TME) and the occurrence of intrinsic and adaptive immune resistance of tumor cells. In recent years, we have rationally engineered a set of bioinspired stimuli-activatable nanotherapeutics to circumvent cancer immune resistance and potentiate cancer immunotherapy. To prompt the development of nanomedicine-based cancer immunotherapy, in this Account we first introduced the mechanisms of intrinsic and adaptive immune resistance from a tumor cell perspective. We then summarized the bioinspired nanomedicine strategies exploited in our laboratory in the past few years to circumvent both the intrinsic and adaptive immune resistance. These nanoparticles were rationally engineered for highly tumor-specific drug delivery of the immunotherapeutics by responding to the endogenous signals of TME including extracellular/intracellular acidity, overexpressed enzymes, glutathione, and reactive species. These nanoparticles caused the intrinsic immune resistance to migrate by restoring tumor-associated antigen presentation on the surface of tumor cells, repolarizing the tumor-associated macrophages, and eliciting antitumor immunogenicity via the induction of the immunogenetic cell death of tumor cells. Meanwhile, these nanoparticles were also loaded with small molecular or macromolecular immune inhibitors to relieve the inducible expression of the immune checkpoints (e.g., programmed cell death of ligand 1 and indolamine 2,3-dioxygenase 1), thereby relieving the adaptive immune resistance. Overviews of the nanomedicine strategies used to cause the immune resistance to migrate by regulating lactate metabolism and lipid peroxidation were also provided. Furthermore, we suggested rational combination strategies according to diverse cancers to mitigate multiple immune resistance. These tactics can be adopted to perpetuate the cancer immunity cycle for clinical therapy of immune-resistant cancer. It is envisaged that TME-activatable bioinspired nanomedicines to bypass immunosuppressive signaling pathways may broaden the clinical impact of cancer immunotherapy.

Beyond Drug Delivery System: Immunomodulatory Layered Double Hydroxide Nanoadjuvants Take an Essential Step Forward in Cancer Immunotherapy

“…Furthermore, the adjuvanticity of LDH doped with nutritional metal cations is also significantly improved, thereby enabling it to induce tumor ICD and evoke potent antitumor immunotherapy. Such drug-free LDH immunomodulators targeting the immunosuppressive physicochemical factors in TME will effectively avoid the genetic limitations and safety risks faced by traditional biological immunotherapeutics, showing great potential to address the adaptive immune resistance and T cell exhaustion at tumor sites. − Meanwhile, LDH exhibits dose-dependent toxicity to tumor cells at a moderate dose (e.g., 100–500 μg/mL) but remains harmless toward normal tissue cells such as macrophages and DCs up to 500 μg/mL . In addition, more extensive biosafety tests toward cardiovascular and complement systems show that LDH has a negligible impact on red blood cell lysis, C5a content, endothelial cells, and vascular smooth muscle cells’ proliferation/viability .…”

Single-Site Nanozymes with a Highly Conjugated Coordination Structure for Antitumor Immunotherapy via Cuproptosis and Cascade-Enhanced T Lymphocyte Activity

“…In certain cases, cancer cells can avoid detection by the immune system, allowing them to persist and proliferate. This is facilitated by the complex extracellular matrix (ECM) present in solid tumors and the expression of multiple immune checkpoints (ICs). , The ECM forms a dense and rigid network comprising various components such as proteins, glycans, polysaccharides, etc., which plays a critical role in promoting tumor progression, metastasis, and resistance to therapy. − The accumulation of cancer-associated fibroblasts (CAFs) and densely cross-linked ECM (particularly collagen) in the TME create obstacles that hinder the penetration of ICD nanoinducers and significantly impede the infiltration of CD8 + T cells. − In addition, it has been reported that the overexpression of cholesterol in the TME might increase endoplasmic reticulum stress in CD8 + T cells and activates the endoplasmic reticulum stress sensor x-box-binding protein 1, which can upregulate the transcription of PD-1 and TIM-3 in T cells. − Although some traditional immune checkpoint blockers (ICBs) including anti-PD-1/PD-L1 and anti-CTLA-4 have been developed, − the low efficacy and immune-related adverse events greatly limit their efficiency. − Therefore, breaking through the ECM barriers and reducing cholesterol content in the TEM may be a promising strategy to enhance the infiltration of immune cells and reduce the expression ICs in CD8 + T cells for recovering its antitumor effects.…”

Biomineralized MnO2 Nanoplatforms Mediated Delivery of Immune Checkpoint Inhibitors with STING Pathway Activation to Potentiate Cancer Radio-Immunotherapy

“…Radiotherapy (RT), as a mainstream cancer treatment method, has been extensively applied in clinical practices. − Apart from directly killing cancer cells, ionizing radiation during RT would cause immunogenic cell death (ICD) and release of tumor antigens that may subsequently boost certain levels of antitumor immune responses. − Immunotherapy such as immune checkpoint blockade (ICB) therapy has made a significant breakthrough in the clinic to treat cancers. − In particular, the combination of RT and ICB therapy has been explored in clinics to inhibit both local tumors and tumor metastasis. − However, the tumor microenvironment (TME) may greatly reduce the killing functions of T cells and promote the immunosuppression by several types of inhibitory immune cells, such as regulatory T cells (Tregs), myeloid-derived suppression cells (MDSCs), and M2 phenotype macrophages, which restrain the antitumor immune responses induced by RT and limit the response rates of ICB therapies. − Therefore, there is urgent clinical demand to develop strategies that can reverse the immune-suppressive TME and simultaneously elicit robust antitumor immunity to realize better therapeutic outcomes.…”