Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy, aiming to harness the immune system to fight cancer, has shown remarkable success. However, the clinical response rates remain low due to the development of drug resistance. This resistance stems from multiple factors: genetic changes in tumor cells that reduce their susceptibility to immunotherapy; and the creation of immunosuppressive microenvironments (TMEs) by tumors, which hinder immune cell infiltration and function. Tumor cells employ several strategies to escape immune destruction, including overexpressing proteins like PD-L1 (inhibiting cytotoxic T lymphocyte activity) and IDO-1 (reducing T cell function). Epigenetic alterations and metabolic changes within tumor cells also contribute to resistance by affecting drug uptake, efflux, and target structure. The heterogeneous TME further complicates treatment, creating a complex barrier against immunotherapy, with various immunosuppressive cells and secreted molecules actively suppressing anti-tumor responses. The need to overcome these challenges necessitates the development of innovative approaches, and smart drug delivery systems (SDDSs) represent a promising strategy to enhance immunotherapy efficacy.

Several recent reviews have documented the progress of SDDS research for cancer immunotherapy. However, a comprehensive discussion of SDDSs' role in overcoming drug resistance in cancer immunotherapy is lacking. This review addresses that gap, focusing on how SDDSs are being used to enhance immunotherapy efficacy in the context of drug resistance. The review categorizes the mechanisms of drug resistance in cancer immunotherapy to provide a framework for understanding the challenges addressed by SDDSs.

This is a review article. The authors systematically examined existing literature on smart drug delivery systems (SDDSs) and their application in overcoming drug resistance in cancer immunotherapy. The review is structured around the various mechanisms of drug resistance in cancer immunotherapy. First, the authors categorized drug resistance mechanisms into tumor cell-intrinsic and tumor cell-extrinsic mechanisms. Tumor cell-intrinsic mechanisms include low drug uptake, high drug efflux, target mutations, low tumor antigenicity, downregulation of MHC-I, dual roles of interferon (IFN) signaling, and regulation of oncogenic signaling pathways. Tumor cell-extrinsic mechanisms involve the actions of immunosuppressive cells (Tregs, MDSCs, TAMs, TANs) within the TME, and metabolic abnormalities in the TME, such as acidity, hypoxia, and the presence of immunosuppressive metabolites. The authors then examined the diverse strategies employed by SDDSs to overcome these resistance mechanisms. They explored SDDS-based approaches in detail, including those that combine immunogenic cell death (ICD) with immunotherapy; reverse immunosuppressive TMEs; regulate IFN and PTEN signaling pathways; and enhance the efficacy of adoptive cell therapy (ACT). For each strategy, the authors present an overview of the underlying principles and showcase representative examples from recent research, illustrating the different design features of SDDSs employed to target specific resistance mechanisms.

The review highlights the potential of SDDSs to address the challenges of drug resistance in cancer immunotherapy. SDDSs overcome drug resistance through multiple mechanisms: **1. Combining Immunogenic Cell Death (ICD) with Cancer Immunotherapy:** SDDSs enhance the delivery of ICD inducers to tumor cells, increasing intracellular drug concentrations. This leads to improved ICD induction, resulting in increased antigen presentation by dendritic cells and enhanced T cell activation. Examples include ER-targeted SDDSs for photodynamic/photothermal therapy and co-delivery systems combining ICD inducers with IDO-1 inhibitors or immune checkpoint inhibitors (ICBs). **2. Reversing the Tumor Immunosuppressive Microenvironment:** SDDSs target immunosuppressive cells (e.g., MDSCs, TAMs) within the TME. Strategies include delivering drugs directly to these cells to inhibit their function, or reprogramming these cells into anti-tumor phenotypes. This approach is further enhanced by targeting extracellular matrix (ECM) components and stromal cells. SDDSs that degrade the ECM improve the penetration of drugs and immune cells into the tumor. **3. Regulating IFN and PTEN Signaling Pathways:** SDDSs are used to modulate the IFN signaling pathway and restore PTEN expression in tumor cells. This approach enhances the efficacy of immunotherapy by improving antigen presentation and reversing immune evasion. This includes targeting STING for IFN-I production. **4. Enhancing the Efficacy of Adoptive Cell Therapy (ACT):** SDDSs are employed to modify immune cells (T cells, NK cells, macrophages) with therapeutic payloads, enhancing their activity and allowing them to overcome immunosuppressive barriers within the tumor. This includes “backpack” strategies where nanoparticles are attached to the surface of immune cells, delivering therapeutic molecules locally within the tumor microenvironment. The use of biomimetic systems further enhances cell-specific delivery, reducing the risk of toxicity.

The findings underscore the significant potential of SDDSs to improve the efficacy of cancer immunotherapy by directly tackling the challenges of drug resistance. SDDSs offer several advantages. Their targeted delivery capabilities increase the local concentration of therapeutic agents in tumors, overcoming issues of low drug uptake and high efflux. Their ability to combine multiple therapeutic agents in a single delivery system allows for synergistic effects and the addressing of multiple resistance mechanisms simultaneously. Furthermore, the ability to target specific cells within the TME, such as immunosuppressive cells, enhances the effectiveness of immunotherapy and allows for precise treatment with minimal side effects. This is especially true for the ‘backpack’ approach used in ACT where the benefits of direct immune cell activation within the tumor are clearly highlighted. The limitations of current SDDSs, however, must be addressed before widespread clinical application can be achieved.

This review provides a comprehensive overview of how SDDSs can overcome drug resistance in cancer immunotherapy. While significant progress has been made, challenges remain, including the development of biocompatible and biodegradable materials, the need for robust preclinical models that accurately reflect human cancer, and the further exploration of SDDS strategies to optimize immune cell function. Future research should focus on addressing these limitations to translate the promise of SDDSs into effective clinical therapies.

The review primarily focuses on preclinical data from animal models. The translatability of these findings to human cancers requires further investigation. The review also acknowledges that some SDDSs contain non-biodegradable components, potentially inducing toxicity. Furthermore, the heterogeneity of cancers, both within and between patients, presents a significant challenge to the development of universally effective SDDSs. Finally, the review primarily presents data from in vitro and in vivo studies in model organisms, which may not fully replicate the complexity of the human immune system and tumor microenvironment.