CircARAP2 controls sMICA-induced NK cell desensitization by erasing CTCF/PRC2-induced suppression in early endosome marker RAB5A.

Natural killer cells (NK) are the "professional killer" of tumors and play a crucial role in anti-tumor immunotherapy. NK cell desensitization is a key mechanism of tumor immune escape. Dysregulated NKG2D-NKG2DL signaling is a primary driver of this desensitization process. However, the factors that regulate NK cell desensitization remain largely uncharacterized. Here, we present the first report that circular RNA circARAP2 (hsa_circ_0069396) is involved in the soluble MICA (sMICA)-induced NKG2D endocytosis in the NK cell desensitization model. CircARAP2 was upregulated during NK cell desensitization and the loss of circARAP2 alleviated NKG2D endocytosis and NK cell desensitization. Using Chromatin isolation by RNA purification (ChIRP) and RNA pull-down approaches, we identified that RAB5A, a molecular marker of early endosomes, was its downstream target. Notably, transcription factor CTCF was an intermediate functional partner of circARAP2. Mechanistically, we discovered that circARAP2 interacted with CTCF and inhibited the recruitment of CTCF-Polycomb Repressive Complex 2 (PRC2) to the promoter region of RAB5A, thereby erasing histone H3K27 and H3K9 methylation suppression to enhance RAB5A transcription. These data demonstrate that inhibition of circARAP2 effectively alleviates sMICA-induced NKG2D endocytosis and NK cell desensitization, providing a novel target for therapeutic intervention in tumor immune evasion.

Challenges of evaluating immunotherapy efficacy in solid tumors.

Immunotherapy is one of the most promising treatments for multiple tumor types. The significant clinical benefits and durable responses of immunotherapy have led to the emergence of various immune-related clinical response patterns that extend beyond those achieved with cytotoxic agents. Various studies investigated the efficacy of immunotherapy, including the effect on tumor size, long-term survival benefits, and the ability to overcome the particularly challenging survival curves tailing phenomenon. The current immune-related methods guidelines, such as immune-related Response Criteria (irRC), immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), immune Response Evaluation Criteria in Solid Tumors (iRECIST), and immune-modified Response Evaluation Criteria in Solid Tumors (imRECIST), could be well-adapted to identify the heterogeneity of responses that appear in patients receiving immunotherapy, such as pseudoprogression (PsPD) and hyperprogressive disease (HPD), and to some extent to overcome the limitation of evaluating the efficacy of immunotherapy on tumor size by imaging. Additionally, a second type of evaluation method was proposed based on survival, which includes milestone analysis and restricted mean survival time. Currently, milestone analysis is a complementary tool to summarize and interpret trial results along with more conventional measures of survival and other less established metrics. A golden standard evaluation method to distinguish the efficacy of immunotherapy may improve the process of imaging and aid survival-based efficacy evaluation in patients with solid tumors.

NK Cell Therapy: A Rising Star in Cancer Treatment.

Immunotherapy has become a robust and routine treatment strategy for patients with cancer; however, there are efficacy and safety issues that should be resolved. Natural killer (NK) cells are important innate immune cells that have attracted increasing attention owing to their major histocompatibility complex-independent immunosurveillance ability. These cells provide the first-line defense against carcinogenesis and are closely related to cancer development. However, NK cells are functionally suppressed owing to multiple immunosuppressive factors in the tumor microenvironment; thus, releasing the suppressed state of NK cells is an emergent project and a promising solution for immunotherapy. As a result, many clinical trials of NK cell therapy alone or in combination with other agents are currently underway. This review describes the current status of NK cell therapy for cancer treatment based on the effector function and releasing the inhibited state of NK cells in the cancer microenvironment.

Mechanisms of Cancer Resistance to Immunotherapy.

Over the last decade, based on the extensive development of preclinical animal studies and clinical trials, the efficacy, and mechanisms of immunotherapy have been fully explored. Significant and lasting clinical responses with immunotherapy provide a new breakthrough treatment for a variety of refractory cancer histologies, which gradually change the treatment pattern of tumors. However, although immune checkpoint inhibitor drugs are promising for achieving longer-term efficacy, their benefits in the overall population are still very low, such as low frequency of response in some common tumor types such as breast and prostate, and heterogeneity in the degree of response among different tumor lesions in the same patient, making immunotherapy with many limitations and challenges. Most patients do not respond to immunotherapy or inevitably develop resistance to treatment after a period of treatment, manifesting with primary resistance or acquired resistance who initially respond to treatment. The mechanisms of tumor immune resistance are very complex and involve multiple aspects such as genes, metabolism, inflammation, and abnormal neovascularization. Currently, many mechanisms of immunotherapy resistance have been characterized, and more continue to be uncovered. These efforts can improve the quality of medical care for cancer diagnosis and treatment, which improve the quality of life of patients, and finally lead to accurate individualized treatment. This review discusses mechanisms of cancer immunotherapy resistance including tumor-intrinsic factors and tumor-extrinsic factors.

Mechanism of tumor immune escape and treatment strategy / 中国肿瘤生物治疗杂志

@# 肿瘤免疫逃逸是肿瘤发生发展的十大特征之一，针对免疫逃逸环节的免疫疗法近年来取得了显著的成功。免疫疗法涉 及多个因素和环节，与肿瘤细胞自身和肿瘤微环境的改变均有相关且机制复杂，目前在临床实践过程中仍面临着不小的挑战。 本文从3个方面介绍了肿瘤免疫逃逸的机制，包括肿瘤自身的改变、肿瘤诱导微环境的改变以及肿瘤微环境促进肿瘤的发展。同 时针对这些机制，将目前的治疗策略进行了梳理，包括免疫检查点抑制剂、CAR-T疗法以及免疫细胞疗法等的困境与进展，旨在 为肿瘤免疫治疗的下一步发展理清思路。

Advances in immunotherapy combined with chemotherapy in the treatment of gastric cancer / 中国肿瘤生物治疗杂志

@#胃癌患者具有相对较高的突变负荷、新抗原基数和肿瘤浸润淋巴细胞，表明其对免疫治疗可能具有潜在应答性，但多 项研究显示，免疫检查点程序性死亡受体1（programmed death protein1, PD-1）抑制剂单药治疗应答率仅为10%~26%。近期，人们 对化疗对机体免疫系统的影响进行了深入探究，证实化疗药物可通过不同免疫调节机制对肿瘤免疫应答产生影响。多项研究显 示，免疫治疗联合化疗药物在提高患者客观缓解率（ORR）和延长生存期方面具有一定成效，联合方案逐渐成为目前晚期胃癌研 究的热点。本文主要阐述化疗药物对肿瘤免疫应答的影响、免疫治疗联合化疗在晚期胃癌中的应用及预测疗效的生物标记物的 进展，以期为胃癌的临床治疗提供参考。