Advances in bioinformatics, genomics, proteomics, and metabolomics have facilitated the development of novel anticancer agents that have decreased side effects and increased safety. Theranostics, systems that have combined therapeutic effects and diagnostic capabilities, have garnered increasing attention recently because of their potential use in personalized medicine, including cancer-targeting treatments for patients. One interesting approach to achieving this potential involves the development of cancer-associated, stimuli-driven, turn on theranostics. Multicomponent constructs of this type would have the capability of selectively delivering therapeutic reagents into cancer cells or tumor tissues while simultaneously generating unique signals that can be readily monitored under both in vitro and in vivo conditions. Specifically, their combined anticancer activities and selective visual signal respond to cancer-associated stimuli, would make these theranostic agents more highly efficient and specific for cancer treatment and diagnosis. This review focuses on the progress of stimuli-responsive turn on theranostics that activate diagnostic signals and release therapeutic reagents in response to the cancer-associated stimuli. The present article not only provides the fundamental backgrounds of diagnostic and therapeutic tools that have been widely utilized for developing theranostic agents, but also discusses the current approaches for developing stimuli-responsive turn on theranostics.

Due to their autosynchronous roles in shaping the anti-tumor immune response, complex immune regulatory networks acting both locally within the tumor microenvironment as well as in its draining lymph nodes play critical roles in the cancer immunotherapy response. We describe herein a thermosensitive co-polymer hydrogel system formed from biocompatible polymers gelatin and Pluronic® F127 that are widely used in humans to enable the sustained release of a nitric oxide donor and antibody blocking immune checkpoint cytotoxic T-lymphocyte-associated protein-4 for efficient and durable anti-tumor immunotherapy. By virtue of its unique gel formation and degradation properties that sustain drug retention at the tumor tissue site for triggered release by the tumor microenvironment and formation of in situ micelles optimum in size for lymphatic uptake, this rationally designed thermosensitive hydrogel facilitates modulation of two orthogonal immune signaling networks relevant to the regulation of the anti-tumor immune response to improve local and abscopal effects of cancer immunotherapy.

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Dual pH and redox-sensitive polymeric NO delivery micelles act as a cytosol-selective NO bomb for efficient anticancer therapy.

The therapeutic inhibition of immune checkpoints, including cytotoxic T lymphocyte-associated protein (CTLA)-4 and programmed cell death 1 (PD-1), through the use of function blocking antibodies can confer improved clinical outcomes by invigorating CD8+ T cell-mediated anticancer immunity. However, low rates of patient responses and the high rate of immune-related adverse events remain significant challenges to broadening the benefit of this therapeutic class, termed immune checkpoint blockade (ICB). To overcome these significant limitations, controlled delivery and release strategies offer unique advantages relevant to this therapeutic class, which is typically administered systemically (e.g., intravenously), but more recently, has been shown to be highly efficacious using locoregional routes of administration. As such, in this paper, we describe an in situ crosslinked hydrogel for the sustained release of antibodies blocking CTLA-4 and PD-1 signaling from a locoregional injection proximal to the tumor site. This formulation results in efficient and durable anticancer effects with a reduced systemic toxicity compared to the bolus delivery of free antibody using an equivalent injection route. This formulation and strategy thus represent an approach for achieving the efficient and safe delivery of antibodies for ICB cancer immunotherapy.

breast cancer (TNBC), which lacks hormone receptor and excess HER2 protein expression, is the most aggressive type of breast cancer, with higher rates of metastasis and shorter overall survival. [3] Immunotherapies have emerged as one of the most promising tools in the fight against breast cancer. However, response rates in the clinic are disappointingly low-only ≈16% of patients respond to immune checkpoint blockade (ICB) therapy, [4] and no vaccine therapies have been approved for breast cancer, despite successes in melanoma and prostate cancer. [5,6] These poor outcomes reflect an unmet need in understanding the differences in patient responses and tools to develop new and better immunotherapeutic strategies for patients who are less likely to respond to immunotherapies.Substantial efforts in the immune oncology field are currently dedicated to unraveling the determinants of the anti-cancer immune response, given its role in disease progression and response to immunotherapy. Immunologically "hot" tumors generally have more immune infiltration, while "cold" tumors harbor fewer immune cells. [7] Additionally, other stratifications have been identified, with the potential to influence immunotherapy responses-among immune-infiltrated (hot) tumors, macrophages, and CD8 T cells have been shown to have opposite impacts on patient survival, and in turn on Immunotherapy has emerged as one of the most powerful anti-cancer therapies but is stymied by the limits of existing preclinical models with respect to disease latency and reproducibility. Additionally, the influence of differing immune microenvironments within tumors observed clinically and associated with immunotherapeutic resistance cannot be tuned to facilitate drug testing workflows without changing model system or laborious genetic approaches. To address this testing platform gap in the immune oncology drug development pipeline, the authors deploy engineered biomaterials as scaffolds to increase tumor formation rate, decrease disease latency, and diminish variability of immune infiltrates into tumors formed from murine mammary carcinoma cell lines implanted into syngeneic mice. By altering synthetic gel formulations that reshape infiltrating immune cells within the tumor, responsiveness of the same tumor model to varying classes of cancer immunotherapies, including in situ vaccination with a molecular adjuvant and immune checkpoint blockade, diverge. These results demonstrate the significant role the local immune microenvironment plays in immunotherapeutic response. These engineered tumor immune microenvironments therefore improve upon the limitations of current breast tumor models used for immune oncology drug screening to enable immunotherapeutic testing relevant to the variability in tumor immune microenvironments underlying immunotherapeutic resistance seen in human patients.

The lymphatic system has gained significant interest as a target tissue to control cancer progress, which highlights its central role in adaptive immune response. Numerous mechanistic studies have revealed the benefits of nano-sized materials in the transport of various cargos to lymph nodes, overcoming barriers associated with lymphatic physiology. The potential of sustained drug delivery systems in improving the therapeutic index of various immune modulating agents is also being actively discussed. Herein, we aim to discuss design rationales and principles of locoregional lymphatic drug delivery systems for invigorating adaptive immune response for efficient antitumor immunotherapy and provide examples of various advanced nanoparticle- and hydrogel-based formulations.