Core Insights - Immune therapy has fundamentally changed the clinical approach to tumor treatment, particularly with PD-1/PD-L1 immune checkpoint inhibitors, which have received continuous FDA approvals for both monotherapy and combination therapy. However, the clinical benefits in advanced tumor patients remain limited due to low somatic mutation rates, few infiltrating lymphocytes, and low PD-L1 expression levels, indicating these tumors are "cold tumors" [2] - Various immune cytokines such as IL-2, IL-7, IL-12, and IL-15 have been identified to regulate T cell proliferation, survival, and function, with the potential to convert "cold tumors" into "hot tumors" and enhance anti-tumor responses when used in conjunction with immune checkpoint inhibitors. Nonetheless, their clinical application faces challenges including technical difficulties, safety concerns, and insufficient efficacy observed in advanced tumors [2] Group 1 - The recent study published in Cell Reports Medicine demonstrates the local delivery of IL-15 and anti-PD-L1 nanobody via in vitro transcribed circILNb, which activates robust anti-tumor immunity in "cold tumors" that are unresponsive to conventional immunotherapy [3][4] - The research team engineered a circCV-B3 vector to achieve scarless circular RNA (circRNA) engineering, allowing circILNb to co-encode IL-15 and anti-PD-L1 nanobody. This circILNb is purified through a biotin-avidin purification system and encapsulated in lipid nanoparticles (LNP) for intratumoral injection, leading to in situ protein expression and activation of existing CD8+ T cells and NK cells for local tumor control [6][8] Group 2 - The study highlights the potential of the circCV-B3 vector and BAPS as circRNA engineering methods, confirming that circILNb can serve as a non-protein therapeutic strategy for tumor immunotherapy [8]

Core Viewpoint - Immunotherapy, particularly immune checkpoint blockade (ICB), has transformed cancer treatment but remains ineffective in "cold tumors" due to immune suppression in the tumor microenvironment (TME) [2][5][6] Group 1: Research Findings - A new biomimetic Ru/TiO₂ nanobiocatalyst system inspired by natural enzyme reaction systems (ERS) has been developed, capable of rapid, pH-dependent generation of reactive oxygen species (ROS) and oxygen (O₂), effectively converting cold tumors into hot tumors [3][6][7] - The Ru/TiO₂ system enhances anti-tumor immunity and suppresses tumor metastasis when used in conjunction with ICB therapy [3][7] - This research establishes a precedent for adaptive nanobiocatalysts in the TME and paves the way for the development of next-generation immunotherapies targeting drug-resistant cancers [3][6] Group 2: Mechanism of Action - The study demonstrates that Ru/TiO₂ can mediate immunogenic cell death (ICD) in melanoma cells through endoplasmic reticulum stress, while also inhibiting hypoxia-induced immune suppression [7] - The design of Ru/TiO₂ aims to reverse immune suppression and enhance immunogenicity, transforming "immune cold" tumors into "immune hot" tumors [7] Group 3: Clinical Implications - The findings suggest that the rational design of robust and efficient biocatalytic materials could extend beyond cancer treatment, opening new avenues for immune modulation in other diseases [3][6]