Immunotherapy has become an important part of the oncotherapy arsenal. Its applicability in various cancer types is impressive, as well as its use of endogenous mechanisms to achieve desired ends. However, off-target or on-target-off-tumor toxicity, limited activity, lack of control in combination treatments and, especially for solid tumors, low local accumulation, have collectively limited clinical use thereof. These limitations are partially alleviated by delivery systems. Lipid-based nanoparticles (NPs) have emerged as revolutionary carriers due to favorable physicochemical characteristics, with specific applications and strengths particularly useful in immunotherapeutic agent delivery. The aim of this review is to highlight the challenges faced by immunotherapy and how lipid-based NPs have been, and may be further utilized to address such challenges. We discuss recent fundamental and clinical applications of NPs in a range of areas and provide a detailed discussion of the main obstacles in immune checkpoint inhibition therapies, adoptive cellular therapies, and cytokine therapies. We highlight how lipid-based nanosystems could address these through either delivery, direct modulation of the immune system, or targeting of the immunosuppressive tumor microenvironment. We explore advanced and emerging liposomal and lipid nanoparticle (LNP) systems for nucleic acid delivery, intrinsic and extrinsic stimulus-responsive formulations, and biomimetic lipid-based nanosystems in immunotherapy. Finally, we discuss the key challenges relating to the clinical use of lipid-based NP immunotherapies, suggesting future research directions for the near term to realize the potential of these innovative lipid-based nanosystems, as they become the crucial steppingstone towards the necessary enhancement of the efficacy of immunotherapy. Graphical abstract

Cancer immunotherapy, a promising and widely applied mode of oncotherapy, makes use of immune stimulants and modulators to overcome the immune dysregulation present in cancer, and leverage the host’s immune capacity to eliminate tumors. Although some success has been seen in this field, toxicity and weak immune induction remain challenges. Liposomal nanosystems, previously used as targeting agents, are increasingly functioning as immunotherapeutic vehicles, with potential for delivery of contents, immune induction, and synergistic drug packaging. These systems are tailorable, multifunctional, and smart. Liposomes may deliver various immune reagents including cytokines, specific T-cell receptors, antibody fragments, and immune checkpoint inhibitors, and also present a promising platform upon which personalized medicine approaches can be built, especially with preclinical and clinical potentials of liposomes often being frustrated by inter- and intrapatient variation. In this review, we show the potential of liposomes in cancer immunotherapy, as well as the methods for synthesis and in vivo progression thereof. Both preclinical and clinical studies are included to comprehensively illuminate prospects and challenges for future research and application.

Endometrial cancer (EC) is the most common gynecological tumor all over the world, and advanced/metastatic EC remains a malignancy with poor survival outcome due to highly resistant to conventional chemotherapeutic treatment. Here, we report that Aurora-A, a serine-threonine kinase, plays a vital role in chemoresistance of EC. Aurora-A is overexpressed in EC tissues, compared with normal endometrium and Aurora-A expression is associated with decreased overall survival. Overexpression of Aurora-A in EC cell lines (Ishikawa and HEC-1B cells) promotes cell proliferation and induced paclitaxel- and cisplatin-resistance. Furthermore, Aurora-A activating AKT-mTOR pathway further induces chemoresistance in vitro, consistent with a positive correlation between Aurora-A and phosphorylated AKT/4E-BP1 expression in EC tissues. In summary, our study provides the strong evidence that Aurora-A controls the sensitivity of EC cell lines to chemotherapy via AKT/mTOR pathway, indicating that pharmacologic intervention of Aurora-A and AKT/mTOR in combination with chemotherapy may be considered for the targeted therapy against EC with overexpression of Aurora-A.

Purpose: Anti-programmed death ligand-1 monoclonal antibody (anti-PD-L1 mAb) therapy has demonstrated notable clinical success. However, efficacy is often limited by transient interactions at the tumor-immune interface, limiting sustained immune activation. To address this, we hypothesized that liposomal delivery of anti-PD-L1 mAbs could enhance therapeutic efficacy. Nanosystems may increase binding avidity and prolong cell-surface retention, and enable multivalent antibody presentation through conjugation of multiple antibodies onto a single liposome. Methods: In this study, we engineered multivalent anti-PD-L1 liposomes (anti-PD-L1 LPs) by conjugating FDA-approved anti-PD-L1 mAbs (atezolizumab) at varying densities onto a clinically relevant liposomal formulation. The biophysical properties, cellular interactions, and therapeutic potential of anti-PD-L1 LPs were evaluated using two melanoma cell line models (BLM and MZ2Mel43), employing multiple analytical techniques. Results: Our results demonstrated that high-density anti-PD-L1 LPs exhibited superior binding avidity, prolonged membrane retention, and reduced non-specific cellular interaction with PD-L1-expressing cells compared to both low-density and non-targeted LPs. Additionally, in 3D tumor spheroid models, high-density anti-PD-L1 LPs showed deeper penetration, suggesting improved tissue accessibility compared with low-density formulations. Moreover, compared to free antibodies, anti-PD-L1 LPs displayed a higher association rate (k_on) and a significantly lower dissociation rate (k_off), resulting in an overall improved (lower) dissociation constant (K_D). Functional assays confirmed that anti-PD-L1 LPs achieved superior PD-L1 blockade compared to free antibodies. Importantly, in co-cultures of human peripheral blood mononuclear cells and tumor cells, anti-PD-L1 LPs maintained immunomodulatory activity comparable to free anti-PD-L1 antibodies. Conclusion: This study highlights the critical role of ligand density in enhancing binding strength, tumor retention, and tissue penetration of the anti-PD-L1 LP system. Our nanosystem offers a promising improvement over conventional anti-PD-L1 mAbs, supporting the broader application of this modular liposomal platform to other therapeutic antibodies in melanoma and other solid tumors. Plain Language Summary: Current limitations and our approach Cancer immunotherapy drugs like anti-PD-L1 antibodies help the immune system fight cancer, but they often do not stay in tumors long enough to work effectively. To improve this, we developed nanoscale lipid-based carriers, like tiny fat bubbles (called liposomes) densely coated with anti-PD-L1 antibodies. These engineered liposomes bind to tumors more effectively, stay longer, and deliver treatment more precisely than regular antibodies. Key discoveries We discovered that packing more drugs onto each tiny carrier makes them stick to tumors better and last longer. Also, how we deliver these drugs matters too—the carrier-delivered versions bind to tumors more effectively than regular antibody drugs. Importantly, in controlled lab tests with cells, these engineered antibodies work just as powerfully as regular immunotherapy—proving we have created a delivery system without sacrificing cancer-fighting strength. Conclusion and potential benefits This research introduces an innovative approach to cancer immunotherapy delivery using antibody-coated liposomes. By enhancing tumor targeting and retention while minimizing accumulation in healthy tissues, this method could improve treatment effectiveness while reducing side effects. The platform offers three key advantages: patients may require fewer treatment sessions with more durable results, clinicians gain enhanced options for treating melanoma and solid tumors, and researchers can extend this adaptable platform to other cancer therapies. Future directions Our immediate focus will be on validating these findings in animal models and expanding the technology to other immunotherapies. The use of clinically approved components positions this approach for potential rapid translation to human trials, pending successful preclinical results.