As one of the most common forms of solid tumours, gastric carcinoma has been revealed as the third leading cause of death worldwide. The symptom of gastric cancer is usually not obvious and thus difficult to detect at earlier stages. Therefore, gastric cancer is already in the advanced stage once detected in patients, which has a poor prognosis due to ineffective therapies and multiple resistance. Recent advance in understanding the microenvironment of cancer has significantly promoted the development of immunotherapy for advanced gastric cancer. Immunotherapy can induce immune responses in gastric cancer patients thus leads to the destruction of cancer cells. In comparison of traditional therapy, immunotherapy has demonstrated robust efficacy and tolerable toxicity. Therefore, this novel strategy for treatment of advanced gastric cancer has gain increasingly popularity. In this review, we summarize recent progress of immunotherapy in advanced gastric cancer, such as immune check point inhibitors, adoptive cell therapy, VEGF inhibitors, cancer vaccines and CAR-T cell therapy. We highlight immunotherapies involved in clinical applications and discuss the existing challenges of current immunotherapies and promising strategies to overcome these limitations.

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.

Background Inhibitors targeting VEGF and VEGFR are commonly used in the clinic, but only a subset of patients could benefit from these inhibitors and the efficacy was limited by multiple relapse mechanisms. In this work, we aimed to investigate the role of innate immune response in anti-angiogenic therapy and explore efficient therapeutic strategies to enhance efficacy of anti-angiogenic therapy against non-small cell lung cancer (NSCLC). Methods Three NSCLC tumor models with responses to VEGF inhibitors were designed to determine innate immune-related underpinnings of resistance to anti-angiogenic therapy. Immunofluorescence staining, fluorescence-activated cell sorting and immunoblot analysis were employed to reveal the expression of immune checkpoint regulator CD47 in refractory NSCLC. Metastatic xenograft models and VEGFR1-SIRPα fusion protein were applied to evaluate the therapeutic effect of simultaneous disruption of angiogenetic axis and CD47-SIRPα axis. Results Up-regulation of an innate immunosuppressive pathway, CD47, the ligand of the negative immune checkpoint regulator SIRPα (signal regulatory protein alpha), was observed in NSCLC tumors during anti-angiogenic therapy. Further studies revealed that CD47 upregulation in refractory lung tumor models was mediated by TNF-α/NF-κB1 signal pathway. Targeting CD47 could trigger macrophage-mediated elimination of the relapsed NSCLC cells, eliciting synergistic anti-tumor effect. Moreover, simultaneously targeting VEGF and CD47 by VEGFR1-SIRPα fusion protein induced macrophages infiltration and sensitized NSCLC to angiogenesis inhibitors and CD47 blockade. Conclusions Our research provided evidence that CD47 blockade could sensitize NSCLC to anti-angiogenic therapy and potentiate its anti-tumor effects by enhancing macrophage infiltration and tumor cell destruction, providing novel therapeutics for NSCLC by disrupting CD47/SIRPα interaction and angiogenetic axis.

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.

Ferroptosis is a novel form of programmed cell death characterized by iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation. The execution of ferroptosis is intricately linked to both iron and lipid metabolism. Intriguingly, iron and lipid metabolism are also pivotal for maintaining the physiological function of immune cells. Research has revealed that ferroptosis can potentiate the immunogenicity of tumor cells and engage in intricate interactions with immune cells. Certain ferroptosis inducers have the capacity to augment the efficacy of immunotherapy by modulating the tumor immune microenvironment. Ferroptosis holds immense potential in cancer immunotherapy and is anticipated to emerge as a novel therapeutic target in the future landscape of cancer treatment. In this review, we primarily delineate the ferroptosis signaling pathways and metabolic processes pertinent to immune cells, and further summarize the roles of ferroptosis in tumor-infiltrating immune cells. Ultimately, we anticipate further elucidation of the mechanisms of ferroptosis in immunotherapy and envision that strategies targeting ferroptosis and immunotherapy will be expeditiously applied in clinical oncology practice.

Background: CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. Methods: The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. Results: In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. Conclusions: Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.