Multimodal Key Anti-Oncolytic Therapeutics Are Effective In Cancer Treatment?

Abstract

Oncolytic virus (OVs) therapy has emerged as a promising modality in cancer immunotherapy, attracting growing attention for its multifaceted mechanisms of tumor elimination. However, its efficacy as a monotherapy remains constrained by physiological barriers, limited delivery routes, and suboptimal immune activation. Phototherapy, an innovative and rapidly advancing cancer treatment technology, can mitigate these limitations when used in conjunction with OVs, enhancing viral delivery, amplifying tumor destruction, and boosting antitumor immune responses. This review provides the first comprehensive analysis of synergistic integration of OVs with both photodynamic therapy (PDT) and photothermal therapy (PTT). It also explores their applications in optical imaging-guided diagnosis and optogenetically controlled delivery. Furthermore, it discusses emerging strategies involving biomimetic virus or viroid-based vectors in conjunction with phototherapy, and delves into the immunomodulatory mechanisms of this combinatorial approach. While promising in preclinical models, these combined strategies are still largely in early-stage research. Challenges such as limited light penetration, delivery efficiency, and safety concerns remain to be addressed for clinical translation. Consequently, the integration of OV therapy and phototherapy represents a compelling strategy in cancer treatment, offering significant promise for advancing precision oncology and next-generation immunotherapies.

Keywords: immunotherapy; oncolytic virus; optogenetics; phototherapy.

Scheme 1

Strategies for enhancing cancer diagnosis and treatment based on oncolytic viral therapy combined with phototherapy.

Figure 1

Comparison of different mechanisms of action of phototherapy. Phototherapy is divided into photothermal therapy, photochemotherapy and photodynamic therapy. Reproduced from Seung Lee J, Kim J, Ye YS, et al. Materials and device design for advanced phototherapy systems. Adv Drug Deliv Rev. 2022;186:114339. Copyright 2022, Elsevier.

Figure 2

Light delivery strategies to overcome deep PDT. Reproduced from Sun B, Bte Rahmat JN, Zhang Y. Advanced techniques for performing photodynamic therapy in deep-seated tissues. Biomaterials. 2022;291:121875. Copyright 2022, Elsevier.

Figure 3

Overview of combined phototherapy and immunotherapy for cancer. When combined, phototherapy and immunotherapy can work synergistically to achieve enhanced control of tumor growth at both the primary tumor site and distant metastatic sites. Reproduced from Wang M, Rao J, Wang M, et al. Cancer photo-immunotherapy: from bench to bedside. Theranostics. 2021;11(5):2218–2231. Copyright The Authors. Creative Commons Attribution Licences.

Figure 4

Oncolytic viruses in combination with immunotherapies. Reproduced from Chattopadhyay S, Hazra R, Mallick A, et al. A review exploring the fusion of oncolytic viruses and cancer immunotherapy: an innovative strategy in the realm of cancer treatment. Biochim Biophys Acta Rev Cancer. 2024;1879(4):189110. Copyright 2024, Elsevier.

Figure 5

OV-aided cancer-immunity cycle. Reproduced from Gujar S, G PJ, Kumar V, et al. Tutorial: design, production and testing of oncolytic viruses for cancer immunotherapy. Nat Protoc. 2024;19(9):2540–2570. Copyright 2024, Springer Nature.

Figure 6

(A) OBP-301 replicates in cancer cells with high-end granase expression and induces cancer-specific cell death after replication. (B) OBP-401 preferentially tags cancer cells with GFP, killing them according to the multiplicity of infection. (C) OBP-301 containing KillerRed has the dual function of adenovirus-mediated killing of cancer cells and PDT. Reproduced from Yano S, Tazawa H, Kishimoto H, et al. Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment. Int J Mol Sci. 2021;22(2):879. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/.

Figure 7

PIOVV nanoparticle complex for the treatment of colorectal cancer and its mechanism. Reproduced from Huang J, Ji L, Si J, et al. Platelet membrane-coated oncolytic vaccinia virus with indocyanine green for the second near-infrared imaging guided multi-modal therapy of colorectal cancer. J Colloid Interface Sci. 2024;671:216–231. Copyright 2024,Elsevier.

Figure 8

Schematic representation of modes of action of an optogenetic oncolytic adenovirus. Reproduced from Malogolovkin A, Egorov AD, Karabelsky A, et al. Optogenetic technologies in translational cancer research. Biotechnol Adv. 2022;60:108005.. Copyright 2022, Elsevier.

Figure 9

Non-invasive PA imaging of BphP1-expressing embryo in vivo. (a) Male LoxP-BphP1 mice were crossed with female Vasa-Cre mice, and the embryos all expressed BphP1. (b) Schematic diagram of PA and ultrasound imaging system: The linear ultrasound array and the focusing rocker share atranslation stage. (c) Ultrasound and angiography images of pregnant mice show multiple embryos at different depths. (d) lVlS images of pregnant mice showed the expressionof BphP1, but no EGFP signal. (e) PAT images of maternal organ hemoglobin and BphP1 signals of seven embryos. (f) Superimposed image of hemoglobin (gray) and BphPl (color) signals. (g) Verification of the photoswitching effect of BphP1 on two embryos. (h) Superimposed image of ultrasound (gray) and BphP1 embryo (color) signals. Reproduced from Kasatkina LA, Ma C, Matlashov ME, et al. Optogenetic manipulation and photoacoustic imaging using a near-infrared transgenic mouse model. Nat Commun. 2022;13(1):2813. Copyright 2022, Nature Communication. Creative Commons Attribution 4.0.

Figure 10

Interaction between virus-like AuNV-MTO particles and cancer cells. Reproduced from Wang Z, Su Q, Deng W, et al. Morphology-mediated tumor deep penetration for enhanced near infrared II photothermal and chemotherapy of colorectal cancer. ACS Nano. 2024;18(41):28038–28051. Copyright 2024, American Chemistry Society.

Figure 11

Schematic diagram of the three-in-one oncolytic system p-Adv-CAT-KR for cancer photodynamic immunotherapy. Reproduced from Wang J, Zhu Y, Chen Y, et al. Three-in-one oncolytic adenovirus system initiates a synergetic photodynamic immunotherapy in immune-suppressive cholangiocarcinoma. Small. 2023;19(34):e2207668. © 2023 Wiley‐VCH GmbH.

Figure 12

Evaluation of the in vivo therapeutic efficacy of the p-Adv-CAT-KR triple-functional oxygen self-supplying oncolytic adenovirus system. (a) Schematic diagram of the tumor regression experiment. (b) Tumor images and volume change curves of each group. (c) Tumor Hif-1α IHC and quantification. (d) Tumor Ki67 IHC and quantification. (e) Changes in body weight of mice in each group. (f-j) Liver biochemical indicators (ALT, AST, ALP, protein, TP). (k-l) Creatinine and urea levels. (m) H&E staining of the heart, lungs, kidneys and liver. Reproduced from Wang J, Zhu Y, Chen Y, et al. Three-in-one oncolytic adenovirus system initiates a synergetic photodynamic immunotherapy in immune-suppressive cholangiocarcinoma. Small. 2023;19(34):e2207668. © 2023 Wiley‐VCH GmbH.