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Monitoring the highly dynamic and complex immune response remains a great challenge owing to the lack of reliable and specific approaches. Here, we develop a strategy to monitor the cascade of tumor immune response through the cooperation of pore‐forming alginate gel with chemoenzymatic proximity‐labeling. A macroporous gel containing tumor‐associated antigens, adjuvants, and pro‐inflammatory cytokines is utilized to recruit endogenous DCs and enhance their maturation in vivo. The mature DCs are then modified with GDP‐fucose‐fucosyltransferase (GDP‐Fuc‐Fuct) via the self‐catalysis of fucosyltransferase (Fuct). Following the migration of the obtained Fuct‐DCs to the draining lymph nodes (dLNs), the molecular recognition mediated interaction of DCs and T cells leads to the successful decoration of T cells with GDP‐Fuc‐azide through the Fuct catalyzed proximity‐labeling. Therefore, the activated tumor‐specific T cells in dLNs and tumors can be identified through bioorthogonal labeling, opening up a new avenue for studying the immune mechanism of tumors in situ. [ABSTRACT FROM AUTHOR]

Immunotherapy has greatly improved outcomes for patients with advanced melanoma, but good predictive biomarkers remain lacking in clinical practice. Although increasing evidence has revealed a vital role of pyroptosis in the tumor microenvironment (TME), it remains unclear for pyroptosis as a predictive biomarker for immunotherapy in melanoma. RNA sequencing data and annotated clinical information of melanoma patients were obtained from four published immunotherapy datasets. LASSO regression analysis was conducted to develop a pyroptosis‐based model for quantifying a pyroptosis score in each tumor. Based on four clinical cohorts, we evaluated the predictive capability of the model using multiple immunotherapeutic outcomes, including clinical benefits, overall survival (OS), and progression‐free survival (PFS). Furthermore, we depicted the distinctive TME features associated with pyroptosis. Compared with the group with low pyroptosis scores, the group with high pyroptosis scores consistently achieved better durable clinical benefits in four independent cohorts and the meta‐cohort. ROC analysis validated that the pyroptosis‐based model was a reliable biomarker for predicting clinical benefits from immunotherapy in melanoma. Survival analyses showed that the group with high pyroptosis scores harbored more favorable OS and PFS than those with low pyroptosis scores. Molecular analysis revealed that tumors with high pyroptosis scores displayed a typical immune‐inflamed phenotype in TME, including enrichment of immunostimulatory pathways, increased level of tumor‐infiltrating lymphocytes, upregulation of immune effectors, and activation of the antitumor immune response. Our findings suggested that the pyroptosis‐related model associated with multiple immune‐inflamed characteristics might be a reliable tool for predicting clinical benefit and survival outcomes from immunotherapy in melanoma. [ABSTRACT FROM AUTHOR]

Oncolytic viruses hold great promise for cancer treatment but their practical applications are seriously impaired by a series of limitations. Herein, an engineered oncolytic adenovirus (OA) is constructed that can boost both the direct oncolysis and antitumor immune response of OA attributed to the increased tumor targeting and low‐pH responsive fusogenic activity. The tumor cell membranes are decorated with vesicular stomatitis virus glycoprotein (VSVG) via vesicular stomatitis virus (VSV) infection and then used to mask OA (V‐M@OA). After systemic administration, the engineered OA can target homologous tumors owing to the homing ability of tumor membranes. Then the unique low‐pH responsive fusogenic activity of VSVG significantly enhances the replication of OA by promoting the whole virus infection process, resulting in remarkable virus‐mediated tumoricidal effects and thus abundant in situ released tumor‐associated antigens (TAAs). Meanwhile, VSVG on V‐M@OA augments the adjuvanticity of OA and thus significantly enhancing the antitumor immune response. The synergism of virus‐mediated killing and immune effects leads to significant tumor inhibition with no obvious side effects. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have shown numerous clinical benefits in multiple cancer types, but good predictive biomarkers are severely lacking. Although increasing evidence has linked Hedgehog (Hh) signaling pathway with tumor development, a systematic investigation for its potential as a biomarker remains elusive. Methods: We collected and analyzed the transcriptional data and clinical outcomes of diverse cancers from the Cancer Genome Atlas and four published ICI datasets. Hh activity was estimated by conducting a single‐sample gene‐set enrichment analysis (ssGSEA) for the Hh‐related genes and calculating the ssGSEA score in each tumor sample. Results: Our findings suggest that tumors with high Hh activity displayed multiple immunosuppressive characteristics, including lack of anti‐tumor response pathways, downregulation of immune effectors, enrichment of immunosuppressive cells and chemokines, and activation of immunosuppressive signaling. Notably, patients in the non‐response group had enriched Hh activity and showed worse overall survival (OS; pooled HR = 1.50, 95% CI = 1.02–2.21, p = 0.039). In the subgroup of high programmed cell death ligand 1 (PD‐L1) expression, patients who harbored high Hh activity displayed a dramatically lower response rate to ICIs and a strikingly worse OS (pooled HR = 2.89, 95% CI = 1.53–5.49, p < 0.001). Conclusion: Increased Hh activity correlates with tumor immunosuppression across diverse cancers. Hh activity is not only a predictive biomarker for resistance to ICIs but can also better predict clinical outcomes in combination with PD‐L1 expression. [ABSTRACT FROM AUTHOR]