Tumor tissues/cells are the best sources of antigens to prepare cancer vaccines. However, due to the difficulty of solubilization and delivery of water‐insoluble antigens in tumor tissues/cells, including water‐insoluble antigens into cancer vaccines and delivering such vaccines efficiently to antigen‐presenting cells (APCs) remain challenging. To solve these problems, herein, water‐insoluble components of tumor tissues/cells are solubilized by 8 m urea and thus whole components of micrometer‐sized tumor cells are reasssembled into nanosized nanovaccines. To induce maximized immunization efficacy, various antigens are loaded both inside and on the surface of nanovaccines. By encapsulating both water‐insoluble and water‐soluble components of tumor tissues/cells into nanovaccines, the nanovaccines are efficiently phagocytosed by APCs and showed better therapeutic efficacy than the nanovaccine loaded with only water‐soluble components in melanoma and breast cancer. Anti‐PD‐1 antibody and metformin can improve the efficacy of nanovaccines. In addition, the nanovaccines can prevent lung cancer (100%) and melanoma (70%) efficiently in mice. T cell analysis and tumor microenvironment analysis indicate that tumor‐specific T cells are induced by nanovaccines and both adaptive and innate immune responses against cancer cells are activated by nanovaccines. Overall, this study demonstrates a universal method to make tumor‐cell‐based nanovaccines for cancer immunotherapy and prevention.

In article number 2104849, Mi Liu and co-workers demonstrate a simple and universal method to prepare therapeutic and preventive cancer nanovaccines based on tumor tissues/ cells. Such nanovaccines show both potent preventive and potent therapeutic efficacy in lung cancer, melanoma, and breast cancer. This universal method can be applied to make tumor-cell-based nanovaccines for cancer immunotherapy and prevention.

Indisulam exhibits antitumor activity against several cancer cells. Although the DCAF15-indisulam-RBM39 axis has been well documented in the inhibition of cancer cell growth, it is unknown whether RBM39 degradation alone is the mechanism of action of indisulam. Here, we verified the inhibitory effect of indisulam on the proliferation of gastric cancer cells and its dependence on DCAF15. Proximity-dependent biotin labeling with TurboID and quantitative proteomics revealed that indisulam indeed promoted the interaction between DCAF15 and RBM39. Immunoblotting and immunofluorescence also revealed that indisulam promoted the ubiquitin-mediated RBM39 degradation and RBM39 colocalized with DCAF15 in the nucleus. DCAF15 knockdown almost completely abolished the indisulam-mediated RBM39 reduction. Further knockdown of RBM39 eliminated the effect of DCAF15 on the proliferation of gastric cancer cells upon indisulam treatment. Immunoblotting of gastric tumor tissues confirmed the downregulation of RBM39 by indisulam. Database analysis unveiled that RBM39 was highly expressed in gastric cancer tissues and its high expression significantly shortened the survival time of gastric cancer patients. Taken together, we demonstrated that indisulam enhanced RBM39 ubiquitination and degradation by promoting its interaction with DCAF15, thus inhibiting the proliferation of gastric cancer cells. This work may provide valuable information for drug discovery through proteolysis targeting chimeras. MS data were deposited in ProteomeXchange (Dataset identifier: PXD024168).

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Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN.