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Review
. 2023 Jan 1;13(1):40-58.
doi: 10.7150/thno.77233. eCollection 2023.

Nanoparticles augment the therapeutic window of RT and immunotherapy for treating cancers: pivotal role of autophagy

Yuan-Hua Wu  1 , Rong-Jane Chen  2 , Hui-Wen Chiu  3   4   5 , Li-Xing Yang  6 , Yung-Li Wang  3 , Yu-Ying Chen  7 , Ya-Ling Yeh  7 , Mei-Yi Liao  8 , Ying-Jan Wang  7   9
Affiliations
Review

Nanoparticles augment the therapeutic window of RT and immunotherapy for treating cancers: pivotal role of autophagy

Yuan-Hua Wu et al. Theranostics. .

Abstract

Immunotherapies are now emerging as an efficient anticancer therapeutic strategy. Cancer immunotherapy utilizes the host's immune system to fight against cancer cells and has gained increasing interest due to its durable efficacy and low toxicity compared to traditional antitumor treatments, such as chemotherapy and radiotherapy (RT). Although the combination of RT and immunotherapy has drawn extensive attention in the clinical setting, the overall response rates are still low. Therefore, strategies for further improvement are urgently needed. Nanotechnology has been used in cancer immunotherapy and RT to target not only cancer cells but also the tumor microenvironment (TME), thereby helping to generate a long-term immune response. Nanomaterials can be an effective delivery system and a strong autophagy inducer, with the ability to elevate autophagy to very high levels. Interestingly, autophagy could play a critical role in optimal immune function, mediating cell-extrinsic homeostatic effects through the regulation of danger signaling in neoplastic cells under immunogenic chemotherapy and/or RT. In this review, we summarize the preclinical and clinical development of the combination of immunotherapy and RT in cancer therapy and highlight the latest progress in nanotechnology for augmenting the anticancer effects of immunotherapy and RT. The underlying mechanisms of nanomaterial-triggered autophagy in tumor cells and the TME are discussed in depth. Finally, we suggest the implications of these three strategies combined together to achieve the goal of maximizing the therapeutic advantages of cancer therapy and show recent advances in biomarkers for tumor response in the evaluation of those therapies.

Keywords: autophagy; immunotherapy; nanomaterials; radiotherapy; tumor microenvironment.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Schematic diagram of abscopal effects induced by RT combined with ICIs. RT can activate the human immune system by inducing ICD from cancer cells. After APC uptake, TAAs released from IR-damaged tumor cells move to lymph nodes, and APCs present the antigens to T cells in lymph nodes via the MHC pathway and its costimulatory signals (CD28, CD80, etc.). CD80 and CD86 can activate T cells by binding to CD28. MHC molecules bind to TCRs and activate tumor killing cells. Activated T cells begin to proliferate in lymph nodes and spread through blood and lymphatic vessels. Finally, the activated T cells migrate to the irradiated tumor and any distant tumor lesions to start their antitumor reaction. During this process, immune checkpoints are responsible for maintaining homeostasis of the immune response. CTLA-4 expressed on activated T cells can compete with CD28. PD-1 expressed on NK and T cells can bind to PD-L1 expressed on APCs, which interferes with T-cell-mediated signal transduction. PD-L1 on cancer cells can also send deceptive messages to prevent the immune system from discovering and killing cancer cells. By combining ICIs, such as antibody therapies against CTLA-4 and PD-1/PD-L1, the immunosuppressive effect can be alleviated, and the abscopal effect can be enhanced.
Figure 2
Figure 2
The benefits of nanotechnology combined with RT and immunotherapy in anticancer therapy. (A) The properties of nanomaterials can provide numerous advantages by using different strategies for combination therapy with RT and immunotherapy. Nanomaterials combined with RT can enhance radiosensitizing and synergistic effects and increase cellular ROS generation and cell cycle arrest. (B) The nanomaterials can also improve cargo delivery in combination with immunotherapy, conjugation with immune checkpoint inhibition antibodies (PD-/PD-L1, CTLA-4, IDO, Ox40 and 4-1BB) or siRNA. Moreover, nanomaterials can increase antitumor efficacy by targeting the TME. (C) For instance, nanomaterials can alter the TME by mediating the transformation of M1/M2 macrophages. (D) Nanomaterials can also improve the hypoxia status in the TME. In general, these strategies of combining nanomaterials with RT and immunotherapy as anticancer therapy provide novel insight into how to design effective therapies.
Figure 3
Figure 3
The autophagy signaling pathway is linked to cancer subjected to various treatments. (A) An overview and schematic depiction of autophagy-related signaling pathways in cancer cells. The mTOR/PI3K/Akt, AMPK, and MAPK signaling pathways are the three major autophagy-related pathways in tumor cells. Abnormal mTOR/PI3K/Akt signaling in cancer cells is related to tumor growth, cancer cell survival and cytoskeletal movement. AMPK is important in regulating energy homeostasis. By supporting energy metabolic processes, AMPK supports cancer cell proliferation. MAPK signaling pathways can be classified into three main families: the ERK, JNK/SAPK and p38 kinase families. (B) An overview and schematic depiction of nanomaterials and their therapeutic implications for RT or immunotherapy. These nanomaterials combined with RT or immunotherapy induced autophagy and caused the death of tumor cells.
Figure 4
Figure 4
Schematic depiction of different cell fates and potential biomarkers of RT combined with immunotherapy. (A) An overview of different types of cell death and cell fate after RT and immunotherapy, including necroptosis, apoptosis, pyroptosis, autophagic cell death (ACD) and cellular senescence. In addition, there is a growing demand for predictive and prognostic biomarkers of RT and immunotherapy. (B) Biomarkers are currently validated for clinical practice and research, including surface marker (PD-1, CTLA-4, etc.) expression in tumor cells and immune cells, neoantigen expression, noninvasive image-based technologies (SPE-CT, PET-CT and MRI), tumor mutation burden (TMB), and exosomes.
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