bims-spamet 2026-10-25 papers

Sci Adv. 2026 Oct 23. 12(43): eadz0039

An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8+ T cells via preserving their mitochondrial fitness.

Yiming Qi, Jing Li, Ziyan Chen, Chenming Zou, Haichao Zhu, Alice Shen Yi Shan, Yuli Fu, Jingwen Hou, Chaozhu Zheng, Qiongzhe Ren, Yu Qiao, Zhu Jin, Feihu Wang, Shengrong Guo.

CD8+ T cell exhaustion driven by mitochondrial dysfunction remains a major barrier to effective cancer immunotherapy. Here, we report an in situ forming d-α-tocopheryl polyethylene glycol succinate (TPGS)-based hydrogel [multifunctional thermosensitive composite gel (MTC Gel)] that reinvigorates exhausted CD8+ T cells by preserving mitochondrial fitness through a two-pronged strategy. After intratumoral injection, MTC Gel rapidly undergoes gelation at physiological temperature and dissociates to generate a high local concentration of TPGS, which targets cancer cell mitochondria to trigger prodeath mitophagy. This process induces robust immunogenic cell death (ICD) and blocks tunneling nanotube-mediated mitochondrial hijacking. Meanwhile, NLG919-loaded hybrid nanoparticles released from MTC Gel synergistically restore mitochondrial biogenesis in CD8+ T cells suppressed by indoleamine 2,3-dioxygenase 1. Across multiple murine tumor models, MTC Gel reprograms T cell immunity by reducing CD8+ T cells exhaustion while enhancing effector and cytotoxic functions, thereby eliciting potent tumoricidal activity. These findings highlight this rationally designed hydrogel system as a clinically translatable platform for next-generation ICD-based cancer immunotherapies.

DOI: https://doi.org/10.1126/sciadv.adz0039

Front Immunol. 2026 ;17 1940201

Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity.

Keith Alan Nair, Jessica Lee, Olivia Zaleski, Luciano Mazzoccoli, Brian Deng, Chih-Chi Andrew Hu, Stanley Ching-Cheng Huang, Andreas Wieland, Hazem E Ghoneim, Haitao Wen, Xiaopei Huang, Bei Liu.

CD8+ T cells play a crucial role in anti-tumor immunity; however, their functionality is compromised by exhaustion driven by chronic antigen exposure, poor tumor microenvironment, and metabolic dysfunction. Activated CD8+ T cells undergo extensive proteomic remodeling, which includes the induction of the IRE1-XBP1 signaling axis of the unfolded protein response. However, the functional consequences of sustained IRE1-XBP1 activation in exhausted CD8+ T cells remain elusive. Using a model of constitutive XBP1 activation in CD8+ T cells, we demonstrate that sustained XBP1s signaling leads to reduced homeostatic CD8+ T cell populations, impaired migratory capacity, and dampened anti-tumor immunity. Notably, pharmacological inhibition of the IRE1-XBP1 axis significantly reduces tumor burden through a dual mechanism that targets both tumor cells and the immune compartment. Our findings reveal a previously unappreciated role for XBP1s in regulating CD8+ T cell biology and highlight the IRE1-XBP1 axis as a therapeutic target in solid tumors.

Keywords: CD8+ T cells; T cell exhaustion; XBP1s; anti-tumor immunity; unfolded protein response

DOI: https://doi.org/10.3389/fimmu.2026.1940201

Front Immunol. 2026 ;17 1865949

From density to spatial function: spatial multi-omics, composite biomarker design, and therapeutic engineering of tertiary lymphoid structures in solid tumors.

Xuchen Wang, Lin Lin.

Background: Tertiary lymphoid structures (TLSs) have emerged as clinically relevant immune niches associated with improved survival and enhanced response to immune checkpoint inhibitors across multiple solid tumors. However, translational evaluation remains dominated by density-based scoring, which inadequately captures the functional heterogeneity of histologically similar lymphoid aggregates. This review synthesizes recent advances in spatial biology that support a shift from counting TLSs to interpreting them as spatially organized immune microenvironmental units embedded within local tumor ecosystems.
Main body: Evidence from spatial transcriptomics, multiplexed imaging, single-cell profiling, computational pathology, and spatial-proteomic approaches converges on four coupled requirements for productive TLS function: stromal licensing through lymphotoxin-dependent chemokine circuits, vascular competence mediated by specialized high endothelial venules, helper T-cell programs that bridge follicular and cytotoxic immunity, and a permissive metabolic context that enables maturation. Spatial studies further show that regulatory infiltration, suppressive plasma-cell programs, and metabolic disruption can decouple structural presence from effective antitumor immunity. Across tumor types, these insights indicate that biomarker performance improves when TLS density is integrated with maturity, anatomical location, HEV coupling, immune composition, and treatment context rather than used as a standalone metric. We further discuss how spatial analyses reveal actionable pathways for inducing or reprogramming TLSs and outline a staged, module-matched composite biomarker workflow combining digital pathology, targeted multiplexed imaging, and focused molecular or metabolic augmentation.
Conclusions: TLSs should be regarded as spatially organized, functionally heterogeneous immune microenvironmental units rather than biologically equivalent lymphoid aggregates. A spatial-functional framework helps explain productive, arrested, and suppressive TLS states, provides a basis for next-generation composite biomarkers, and supports module-matched therapeutic strategies tailored to the stromal, vascular, helper-cell, or metabolic bottleneck limiting TLS function in individual tumors. The immediate next step is prospective validation of a minimal TLS panel across defined treatment contexts.

Keywords: B cells; composite biomarkers; high endothelial venules; immunotherapy; multiplexed imaging; spatial transcriptomics; tertiary lymphoid structures; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1865949