Indian Institute of Chemical Biology (IICB) is a biomedical research centre in Kolkata, West Bengal, India. Established in 1935 as Indian Institute of Experimental Medicine (IIEM), it was inducted under the aegis of Council of Scientific & Industrial Research (CSIR) in 1956 and renamed to its present form in 1982. It has 6 R&D divisions:- Cancer Biology & Inflammatory Disorder, Cell Biology & Physiology, Chemistry, Infectious Diseases & Immunology, Molecular & Human Genetics, and Structural Biology & Bioinformatics..
The persistence of CAR T cells and antigen escape remain major barriers to durable therapeutic success in hematologic malignancies. Our study integrates AI-guided design with targeted protein degradation to overcome these challenges. Utilizing an in-silico library of CAR constructs followed by an in vitro screening, we developed a predictive model, CARMSeD, which forecasts constructs prone to self-activation and dysfunction. Optimized bispecific CD20/CD19 CAR T cells demonstrate superior persistence and anti-tumor efficacy. To further improve durability, the platform incorporates a PROTAC-based module that selectively degrades AKT3, promoting FOXO4-driven mitochondrial fitness, central memory differentiation, and reduced mTOR signaling. We extended this strategy to develop a trispecific CAR T platform co-expressing a secretable CD3/CD22 bispecific engager, achieving potent tumor eradication even in CD19/CD20-negative malignancies demonstrates efficacy across patient-derived leukemia samples and solid tumor models. Together, our study introduces a next-generation AI-guided CAR T strategy that integrates structure-based optimization and intracellular modulation to improve persistence, broaden antigen coverage, and ensure durable therapeutic efficacy. Durable, multi-antigen CAR T responses in B-cell malignancies are in need. The authors here demonstrate that AI-guided CAR designs combined with targeted pathway modulation enhance persistence, prevent antigen escape, and improve anti-tumor efficacy.
Abstract Sphingosine-1-phosphate receptor 1 (S1PR1) signaling has been linked to the regulation of immunosuppressive cell populations within the tumor microenvironment (TME); however, its role in shaping anti-tumor CD8⁺ T cell responses remains poorly defined. Herein, we demonstrate that intratumoral CD8⁺ T cells express S1PR1, with expression predominantly enriched in the terminally exhausted subset. Transcriptomic profiling, combined with pharmacological inhibition and genetic knockdown, reveals that S1PR1-S1P signaling activates the PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase)-CHOP (C/EBP homologous protein) axis of the endoplasmic reticulum stress response. CHOP, in turn, upregulates transcription of Map3k13 and Map3k15, triggering downstream MAPK signaling and culminating in activation of p38MAPK. Activation of this pathway impairs CD8⁺ T cell metabolism and effector function while increasing apoptotic susceptibility. This ultimately limits the persistence and accumulation of functional CD8⁺ T cells within the TME, thereby compromising their responsiveness to anti-PD-1 therapy. Targeting the S1PR1-S1P axis or its downstream effectors offers a promising strategy to improve cancer immunotherapy outcomes.
Chromosomes are folded hierarchically into compartments, domains, and chromatin loops within the three-dimensional (3D) nuclear space. Despite their relevance for agriculture, little is known about the 3D genome architecture of the plant pathogenic oomycetes and their potential influence on gene regulation and pathogenicity. To address this, we generated a chromosome-scale reference genome and elucidated the 3D genome organization of the multi-host phytopathogenic oomycete Phytophthora capsici for the first time. The P. capsici genome has 17 chromosomes with Rabl configuration, with non-random inter-chromosomal interactions. Each chromosome separates into a core, gene-rich, transcriptionally active ‘A’ compartment and a repeat-rich, pathogenic ‘B’ compartment with a higher evolutionary rate. Topologically associated domains (TADs) are prominent with transcriptionally active, gene-rich boundaries that coincide with accessible open chromatin regions. Genes within each TAD exhibit stage-specific co-expression, indicating these motifs serve as functional regulatory units. P. capsici harbors chromatin loops similar to those in mammals. However, no CTCF binding sites are present. Instead, a strong over-representation of intergenic zf-C2H2 binding regions at loop anchors, a pattern consistent with observations in microbial eukaryotes, is revealed. Altogether, these findings provide a comprehensive view of the three-dimensional genome architecture of oomycetes, advancing our understanding of the underlying mechanistic insights.
The heterogeneity in patient responses to immune checkpoint blockade (ICB) is dictated by the relative abundance of exhausted CD8⁺ T cell (Tex) subsets with distinct therapeutic responsiveness. Progenitor exhausted (pTex) cells remain sensitive to ICB, whereas terminally exhausted (tTex) cells are refractory; however, the molecular cues that bias differentiation toward these divergent fates remain poorly defined. Here, we identify the RNA methyltransferase Mettl3 as a central regulator of Tex fate. Across murine tumor models, human T cells, and adoptive transfer systems, Mettl3 expression is selectively enriched in tTex cells and inversely correlated with TCF1⁺ pTex populations. Mechanistically, Mettl3 drives terminal exhaustion by stabilizing DNMT3B transcripts via m⁶A modification, enforcing CpG methylation and chromatin compaction at memory-associated loci. Inhibition of the Mettl3-Dnmt3b axis reprograms chromatin accessibility toward memory-like states, thereby preserving progenitor potential and effector function. Consequently, T cells lacking Mettl3-Dnmt3b activity persist longer, mount robust recall responses, and achieve superior tumor control with enhanced responsiveness to PD-1 blockade. These findings establish the Mettl3-m⁶A-Dnmt3b axis as a molecular rheostat of CD8⁺ T cell fate, coupling epitranscriptomic regulation to epigenetic remodeling, and reveal a tractable pathway to improve the durability of cancer immunotherapy. ### Competing Interest Statement The authors have declared no competing interest. Wellcome Trust/DBT India Alliance, https://ror.org/04reqzt68, IA/I/19/1/504277
ABSTRACT The increasing prevalence of fungal phytopathogens and the widespread emergence of fungicide resistance necessitate the development of alternative antifungal strategies with reduced environmental impact. Here, we report the isolation and characterization of a novel antifungal metabolite, SM06, produced by the rice seed-associated endophytic bacterium Phytobacter sp. RSE02. SM06 exhibited broad-spectrum antifungal activity against plant and human pathogenic fungi, including Curvularia lunata, Fusarium oxysporum, and Candida albicans. In vitro assays and micromorphological analyses revealed that SM06, an indole dimer, disrupts fungal cell membrane integrity, while in planta experiments demonstrated significant suppression of brown leaf spot disease in tomato and rice. Molecular docking suggested that SM06 binds to lanosterol 14α-demethylase (ERG11), a key enzyme in fungal sterol biosynthesis. Consistent with this prediction, LC-MS–based analyses confirmed a significant reduction in ergosterol content in SM06-treated fungal cells. Together, these findings identify SM06 as a biologically active antifungal metabolite produced by a plant-associated bacterium, highlighting its potential application in sustainable fungal disease management.IMPORTANCEFungal diseases cause major losses in crop production and contribute to the growing challenge of antifungal resistance, underscoring the need for sustainable alternatives to chemical fungicides. This study identifies SM06, a novel indole dimer produced by the rice seed endophyte Phytobacter sp. RSE02, with strong antifungal activity against economically important plant pathogens and clinically relevant fungi. Through integrated chemical, cellular, and in planta analyses, we demonstrate that SM06 disrupts fungal membrane integrity by inhibiting ergosterol biosynthesis. The compound is biocompatible, stable, and effective in plant disease suppression, highlighting its translational potential for crop protection. These findings reveal seed endophytes as an important yet underexplored source of antifungal metabolites and provide a mechanistic foundation for developing eco-friendly biocontrol strategies with implications beyond agriculture.
