Advances in Immunogenic Cell Death for Cancer Immunotherapy

The concept of immunogenic cell death (ICD) was originally coined by Kroemer in 2005, demonstrating that tumor cells treated with doxorubicin (DOX) activated the host immune system during apoptosis. ICD is characterized by the release and enhanced expression of adjuvant-like damage-associated molecular patterns (DAMPs), which includes but is not limited to surface-exposed calreticulin (ecto-CRT) exposure, ATP secretion, high mobility group protein B1 (HMGB1) release, and so forth. ICD could establish the specific dialog between dying cells and immune cells to activate an adaptive immune response. In specific, these released DAMPs send out “eat me” and “find me” signals that promote dendritic cell (DC) maturation and tumor antigen presentation, ultimately leading to tumor-specific T cell-mediated antitumor immune responses. In addition, ICD process could also enhance infiltration of T cells into the tumor tissues and regulate immunosuppressive tumor microenvironment (ITM) to be more susceptible to immunotherapy. In this regard, the development of ICD immunotherapy, which combines the direct cancer killing, antitumor immunity and potential immunological memory has generated significant interests in cancer immunotherapy as a promising approach for achieving complete cancer elimination and long-term protective immune responses. The discovery of ICD has revolutionized our understanding and management of cell death and antitumor immunity. With the paradigm shift from nonspecific cytotoxic agents to targeted and specific immunotherapy, ICD-based cancer immunotherapy has entered a new era, with remarkable progresses made in recent decades. Nowadays, the scope of ICD inducers has expanded beyond conventional chemo drugs such as DOX or Carfilzomib, to include immunoregulatory biomaterials, biomimetic active materials, as well as supramolecular assemble peptides and so forth. Apart from chemotherapy, other therapeutic modalities including photodynamic therapy, photothermal therapy, radiation therapy, as well as electromagnetic energy have shown significant potentials in eliciting robust and remarkable ICD antitumor immune response in a spatiotemporal control manner. Moreover, extensive efforts with great advances have also been made in overcoming biological barriers to deliver ICD inducers or vaccines to improve ICD based cancer immunotherapy. We are now witnessing the emergence of a library of new ICD vaccines, ICD induction approaches, and smart delivery systems for cancer immunotherapy, giving rise to the hope and possibility of a completely cure of cancers. To shine light on ongoing and future applications of ICD-based cancer immunotherapy, we organized this Special Issue entitled “Advances in Immunogenic Cell Death for Cancer Immunotherapy”, which attempts to consolidate key recent developments in biomaterials, smart-responsive nano systems, and strategies for provoking ICD for enhanced cancer immunotherapy. This special issue contains 14 reviews and 12 research articles contributed from a number of esteemed experts in this research field, which not only discuss the past, present and future of ICD-based cancer immunotherapy, but also present new techniques that enhance cancer immunotherapy from different perspectives. As a key type of cell death, ICD itself differs from other programmed cell deaths (PCD), and the investigation of ICD induction mechanism and key steps in ICD immune responses lays the foundation for developing ICD inducers, vaccines, and adjuvants. Jun Lin and co-workers (article number 2201406) discussed the critical interrelationship between PCD and ICD and provided unique insights for developing nanomedicines to promote ICD-based tumor immunotherapy. Jianxun Ding et al. (article number 2300204) reviewed the development of ICD-inducing biomaterials, with specific emphasis on ICD induction mechanisms, such as triggering endoplasmic reticulum oxidative stress, mitochondrial dysfunction, and cell membrane rupture, et al. While, Qiangbin Wang (article number 2201457) summarized the recent advances of nano-biomaterials in enhancing ICD from the perspective of key steps in ICD processes. An original research work from Wenbin Lin et al. (article number 2201437) reported a nanoscale coordination polymer to co-deliver oxaliplatin (OX), gemcitabine (GC), and 5-carboxy-8-hydroxyquinoline for a triple-modality chemo-immunotherapy treatment of colorectal carcinoma and triple negative breast cancer. Ying Liu et al. (article number 2201569) coated doxorubicin (DOX)-induced ICD tumor cell membrane on iron (II)-CpG to co-deliver tumor-associated antigens and adjuvant for personalized lung cancer immunotherapy. Dan Ding et al. (article number 2201409) designed a fluorinated supramolecular strategy and developed arginine and fluorinated diphenylalanine peptide based peptide adjuvants to induce antitumor immunity towards ovalbumin lymphoma. Additionally, Xiqun Jiang and coworkers (article number 2201404) elaborated these biomaterials with intrinsic immunoregulatory effects in cancer immunotherapy, while Lintao Cai et al. (article number 2201412) outlined these engineering biomimetic active materials guided physiotherapy, chemotherapy, and biotherapy for ICD induction. Apart from these above discussed ICD vaccines or adjuvants, the ICD process and antitumor immunity could also be elicited by external stimuli, such as light, radiation, or electromagnetic energy, which possess the merits of on demand therapeutic activation, high spatiotemporal control and minimal damage to normal tissues. Liangfang Zhang (article number 2300252) comprehensively reviewed the recent advances of nanoparticle-based photo-immunotherapy for cancer treatment, while Duo Mao et al. (article number 2201614) and Hui Chao et al. (article number 2201403) provided additional insights and discussions from the perspectives of the recent developments of organic photosensitizers and metal-based photosensitizers for photodynamic-immunotherapy, respectively. Original research works aiming to improve the ICD photo-immunotherapy efficacy are also included in this Special Issue. For example, Dan Ding et al. (article number 2201582) developed a smart one-for-all nano agent that could switch the absorbed light energy for maximal either photoacoustic imaging or ICD induction, and combined image-guided tumor secretion and photodynamic-immunotherapy for improve cancer treatment outcome. Yaping Li et al. (article number 2200898) developed a matrix metalloproteinase-2 (MMP-2)-sensitive tumor-penetrable nanovesicle to regulate cholesterol metabolism pathway for enhancing photodynamic cancer immunotherapy. Contributions to improve photothermal-immunotherapy are also presented. Yu Chen and coauthors (article number 2300116) introduced the T-cell activators of anti-CD3 and anti-CD28 monoclonal antibodies to polypyrrole-based magnetic nanomedicines, which demonstrated robust and long-lasting T-cell activation and effective immunosuppressive tumor microenvironment (ITM) regulation after NIR-light activation. Zhiyong Qian et al. (article number 2201087) developed a dual toll-like receptor (TLR) agonists delivery system (CPG@Au NRs/m-R848) based on gold nanorods and polymer micelles for synergistic photothermal immunotherapy of melanoma. In addition, some new strategies with increased deep-tissue ICD induction capability are also presented, Kai Yang et al. (article number 2201401) introduced the recent advances in radiation-induced ICD for cancer radioimmunotherapy, and Kanyi Pu et al. (article number 2201083) summarized the combinations of deep-tissue electromagnetic energy with nanomedicines for inducing ICD and cancer immunotherapy. Importantly, a substantial part of the issue is dedicated to design of novel delivery systems of ICD inducers or vaccines to enhance ICD immunotherapy. For instance, Leaf Huang et al. (article number 2201307) described these delivery barriers to chemical ICD inducers and highlighted recent nanoformulations for safe, effective, and specific delivery of ICD inducers in tumor immunotherapy. Juyong Yoon and coworkers (article number 2201381) summarized the developments of stimuli-responsive smart nanomaterials for increasing tumor accumulation efficiency of ICD inducers. To address the biological barriers of cancer-associated fibroblasts (CAFs) that prevents drug delivery and T cell infiltration into tumors, Shaobing Zhou and coworkers (article number 2201327) developed a pH-responsive dendritic nanoliposome as a in situ vaccine to reduce CAF activity, elicit ICD, revise immunosuppressive tumor microenvironment (ITM) for enhanced chemo-immunotherapy. Haijun Yu et al. (article number 2200888) developed an intracellular acidity and oxidation dual-responsive nanoparticles to co-deliver dihydroartemisinin (DHA) and RSL-3 (a glutathione peroxidase 4 (GPX4) inhibitor) for the induction of tumor cell ferroptosis and T-cell based antitumor immunity. Fu-Jian Xu et al. (article number 2201595) reported a nanohybrid based autologous nanovaccine to deliver the model antigen ovalbumin for personalized tumor treatment taking advantage of in situ released tumor-associated antigens induced by ICD. Linqi Shi et al. (article number 2201051) reported a holdase/foldase mimetic nanochaperone (H/F-nChap) for a safe and spatiotemporal delivery of αCD16 and αPDL1 monoclonal antibodies, and resiquimod (R848) for improved cancer immunotherapy. Apart from conventional delivery system, DNA or peptides have also shown promising potentials in ICD immunotherapy. Baoquan Ding et al. (article number 2201518) summarized these intelligent DNA nanoplatforms for delivery of ICD inducers, adjuvants and vaccines, immune checkpoint blockers for immune cell engineering and adoptive cell therapy. Xuehai Yan et al. (article number 2201708) emphasized on the recent progress of supramolecular assembled bioactive peptide nanodrugs as intelligent delivery systems, direct ICD inducers, or immune response enhancers for improving the efficacy of ICD-induced cancer immunotherapy. A multifunctional enzyme-instructed self-assembling peptide nanomedicine was reported by Zhimou Yang et al. (article number 2201416) which specifically delivered lonidamine (LND) to the mitochondrial of cancer cells to induce abundant mitochondrial oxidative stress and provoke robust ICD response. This special issue has showcased many exciting recent progresses in the field of ICD cancer immunotherapy and discussed the challenges and further perspectives from various angles. By providing a broad picture of ICD cancer immunotherapy, we hope to inspire more exciting works in this rapidly growing research field. We also hope that this special issue will encourage more interaction and collaboration among scientists and clinicians across diverse disciplines. We would like to thank all the authors for their exceptional contributions, which reflect the current state-of-the-art in this filed. We also extend our appreciation to Dr. Emily Hu, the Editor-in-Chief, as well as other editors in Small Methods for their valuable support and commitment. Dan Ding received a Ph.D. degree from the Department of Polymer Science and Engineering in Nanjing University in 2010. After a postdoctoral training in the National University of Singapore, he joined Nankai University, where he is currently a professor in the Frontiers Science Center for Cell Responses, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Science. He also conducted his work at The Hong Kong University of Science & Technology as a visiting scholar. His current research focuses on the design and synthesis of smart/functional molecular imaging probes and exploration of their biomedical applications. Xiqun Jiang has been working at the School of Chemistry and Chemical Engineering, Nanjing University since 1986. He received his Ph.D. in polymer materials and engineering from Nanjing University in 1998. His research interests include macromolecule self-assembly, molecular imaging probe, polymer drug delivery systems, and precise modification and biomedical applications of peptide- or protein-based biomaterials.