The recent successes of tumor immunotherapy approaches, such as immune checkpoint blockade (ICB) and chimeric antigen receptor T cell (CAR-T) therapy, have revolutionized cancer treatment, improving efficacy and extending treatment to a larger proportion of cancer patients. However, due to high heterogeneity of cancer, poor tumor cell targeting, and the immunosuppressive status of the tumor microenvironment (TME), combinatorial agents are required to obtain more effective and consistent therapeutic responses in a wide range of cancers. Oncolytic viruses (OVs) are able to selectively replicate in and destroy tumor cells and subsequently induce systematic anti-tumor immune responses. Thus, they are ideal for combining with cancer immunotherapy. In this review, we discuss the current understanding of OVs, as well as the latest preclinical and clinical progress of combining OVs with cancer immunotherapies, including ICB, CART therapy, bispecific T cell engagers (BiTEs), and cancer vaccines. Moreover, we consider future directions for applying OVs to personalized cancer immunotherapies, which could potentially launch a new generation of cancer treatments.

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Tumor-associated macrophages (TAMs) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune checkpoint inhibitors (ICIs) in different cancers, including gastric cancer (GC). Dickkopf-1 (DKK1) associates with tumor progression and has been shown to negatively regulate anti-tumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression closely associated with worse survival and a suppressive TIME in GC patients. Results from in vitro co-culture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting anti-tumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic GC mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced growth of human GC tumors with high DKK1 expression in a xenograft model. Mechanistically, DKK1 interacted with cytoskeleton-associated protein 4 (CKAP4) on the macrophage surface and activated downstream PI3K-AKT signaling, which contributed to immune suppression. TAM reprogramming by DKK1 blockade also augmented the efficacy of programmed cell death protein-1 (PD-1) blockade in GC models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive anti-tumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in GC.

Monolayer molybdenum disulfide (MoS2) nanoenzymes exhibit a piezoelectric polarization, which generates reactive oxygen species to inactivate tumors under ultrasonic strain. However, its therapeutic efficiency is far away from satisfactory, due to stackable MoS2, quenching of piezo‐generated charges, and monotherapy. Herein, chitosan‐exfoliated monolayer MoS2 (Ch‐MS) is composited with atomic‐thin MXene, Ti3C2 (TC), to self‐assemble a multimodal nanoplatform, Ti3C2‐Chitosan‐MoS2 (TC@Ch‐MS), for tumor inactivation. TC@Ch‐MS not only inherits piezoelectricity from monolayer MoS2, but also maintains remarkable stability. Intrinsic metallic MXene combines with MoS2 to construct an interfacial Schottky heterojunction, facilitating the separation of electron–hole pairs and endowing TC@Ch‐MS increase‐sensitivity magnetic resonance imaging responding. Schottky interface also leads to peroxidase mimetics with excellent catalytic performance toward H2O2 in the tumor microenvironment under mechanical vibration. TC@Ch‐MS possesses the superior photothermal conversion efficiency than pristine TC under near‐infrared ray illumination, attributed to its enhanced interlaminar conductivity. Meanwhile, TC@Ch‐MS realizes optimized efficiency on tumor apoptosis with immunotherapy. Therefore, TC@Ch‐MS achieves an integrated diagnosis and multimodal treatment nanoplatform, whereas the toxicity to normal tissue cells is negligible. This work may shed fresh light on optimizing the piezoelectric materials in biological applications, and also give prominence to the significance of intrinsic metallicity in MXene.