Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor-specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor-specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications.

Poor permeation of therapeutic agents and multidrug resistance (MDR) in solid tumors are the two major challenges that lead to the failure of the current chemotherapy methods. Herein, a zero‐waste doxorubicin‐loaded heparin/folic acid/l‐arginine (HFLA‐DOX) nanomotor with motion ability and sustained release of nitric oxide (NO) to achieve deep drug penetration and effective reversal of MDR in cancer chemotherapy is designed. The targeted recognition, penetration of blood vessels, intercellular penetration, special intracellular distribution (escaping from lysosomes and accumulating in Golgi and nucleus), 3D multicellular tumor spheroids (3D MTSs) penetration, degradation of tumor extracellular matrix (ECM), and reversal of MDR based on the synergistic effects of the motion ability and sustained NO release performance of the NO‐driven nanomotors are investigated in detail. Correspondingly, a new chemotherapy mode called recognition‐penetration‐reversal‐elimination is proposed, whose effectiveness is verified by in vitro cellular experiments and in vivo animal tumor model, which can not only provide effective solutions to these challenges encountered in cancer chemotherapy, but also apply to other therapy methods for the special deep‐tissue penetration ability of a therapeutic agent.

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, CAR-T 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.

Tumor-associated macrophages (TAM) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune-checkpoint inhibitors (ICI) in different cancers, including gastric cancer. Dickkopf-1 (DKK1) is associated with tumor progression and has been shown to negatively regulate antitumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression is closely associated with worse survival and a suppressive TIME in gastric cancer patients. Results from in vitro coculture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting antitumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic gastric cancer mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced the growth of human gastric cancer 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 gastric cancer models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive antitumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in gastric cancer.