肿瘤细胞治疗研究
英文原题：A PRK-armed oncolytic adenovirus drives calreticulin exposure for dendritic cell licensing to prime antitumor CD8⁺ T cells and synergizes with anti-PD-1 or CAR-T therapy in colorectal cancer.
我们的工作阐明了一条独特的免疫调节轴——AKT-IP3R3-Ca 2 -CRT，用于逆转腺病毒诱导的免疫抑制。这提供了一种可转化的、基于机制的策略，将免疫学上的「冷」肿瘤转变为对免疫治疗敏感的环境，从而提供一种合理的联合方案以克服耐药性，并显著拓宽当前免疫治疗的适用范围。
溶瘤腺病毒（ADVs）在结直肠癌中的治疗潜力受到一种适得其反的宿主反应的制约：病毒触发的促生存 AKT 通路过度激活，进而塑造出免疫抑制性肿瘤微环境。
我们构建了一种新型溶瘤腺病毒ADV-PRK，旨在共表达AKT抑制肽PRK。其抗肿瘤疗效和机制在同系（MC38、CT26）和人源化小鼠模型中进行了评估。分子分析（Western blot、免疫荧光和qPCR）阐明了信号通路。通过流式细胞术和体外共培养实验评估了免疫学结果。与anti-PD-1或CAR-T细胞的联合治疗在体内进行了测试。
我们证明 ADV-PRK 消除 AKT 及其下游效应分子 ER 钙通道 IP3R3 的磷酸化。这种抑制驱动 ER 钙外流，诱导钙网蛋白 (CRT) 易位至细胞表面。表面暴露的 CRT 作为强效的“eat-me”信号，许可树突状细胞致敏并激活肿瘤特异性 CD8 T 细胞，这对疗效至关重要。在体内，ADV-PRK 单药治疗实现了优越的肿瘤控制。它与抗 PD-1 和 CAR-T 细胞疗法均表现出强效协同作用，通过重塑免疫景观以扩增可激活的 T 细胞并支持过继性细胞疗法。其在人源化模型中的活性证实了转化相关性。
BACKGROUND: The therapeutic potential of oncolytic adenoviruses (ADVs) in colorectal cancer is constrained by a counterproductive host response: virus-triggered hyperactivation of the pro-survival AKT pathway, which fosters an immunosuppressive tumor microenvironment. METHODS: We engineered a novel oncolytic adenovirus, ADV-PRK, designed to co-express the AKT-inhibitory peptide PRK. Its antitumor efficacy and mechanisms were evaluated in syngeneic (MC38, CT26) and humanized mouse models. Molecular analyses (Western blot, immunofluorescence, and qPCR) elucidated signaling pathways. Immunological outcomes were assessed via flow cytometry and in vitro co-culture assays. Combination therapies with anti-PD-1 or CAR-T cells were tested in vivo. RESULTS: We demonstrate that ADV-PRK abrogates phosphorylation of both AKT and its downstream effector, the ER calcium channel IP3R3. This suppression drives ER calcium efflux, inducing calreticulin (CRT) translocation to the cell surface. Surface-exposed CRT acts as a potent "eat-me" signal, licensing dendritic cells to prime and activate tumor-specific CD8 T cells, which are essential for efficacy. In vivo, ADV-PRK monotherapy achieved superior tumor control. It demonstrated potent synergy with both anti-PD-1 and CAR-T cell therapy, by remodeling the immune landscape to expand activatable T cells and support adoptive cellular therapy. Its activity in a humanized model confirms translational relevance. CONCLUSIONS: Our work delineates a distinct immunomodulatory axis, AKT-IP3R3-Ca 2 -CRT, to reverse adenovirus-induced immunosuppression. This provides a translatable, mechanism-based strategy to convert immunologically "cold" tumors into environments receptive to immunotherapy, thereby offering a rational combinatorial approach to overcome resistance and significantly broaden the applicability of current immunotherapies.
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