Our Research | Cell Stress & Immunity

Our Research Philosophy & Vision

Decoding the cellular stress–immunity dialogue to overcome cancer immunotherapy resistance: Life is a continuous dialogue between cellular stress and immunity. Throughout our lifetime, cells encounter diverse environmental, metabolic, and physiological challenges. To maintain tissue health, they activate protective mechanisms that promote adaptation, repair, or controlled cell death. When these safeguards are insufficient, cells communicate with the immune system to eliminate threats, resolve inflammation, and restore tissue homeostasis. This dynamic, reciprocal interplay forms the foundation of what we call the cellular stress–immunity cycle (Figure 1).

Figure 1: Our research philosophy progresses from the cell stress–immunity cycle to translational cancer immunology. Schematic overview of our laboratory’s research vision, centered on the reciprocal interactions between cancer cell stress, cell death, inflammatory responses, and anti-tumour immunity. Our research integrates three interconnected pillars: (1) Fundamental mechanisms, including proteotoxic stress, T-cell signaling and mechanics, immunogenic versus tolerogenic cell death, innate sensing, interferon responses, and antigenicity; (2) Immune ecosystems, focusing on immunotherapy-refractory tumour microenvironments, T-cell functional states, myeloid heterogeneity, and primary versus metastatic niches; and (3) Systems immunology and reverse translation, integrating human immunology, spatial and multicellular immune interactions, and immunotherapy-relevant causality with iterative experimental validation in human-derived and mouse models. Together, these approaches aim to uncover immunotherapy-relevant causal mechanisms and guide the development of more precise, mechanism-driven cancer immunotherapies.

Cancer fundamentally hijacks this protective cycle. Cancer cells exploit stress responses to survive, proliferate, and metastasize while manipulating immune and wound healing-like mechanisms to escape elimination. These disruptions extend beyond cancer cells, reshaping the entire tumour ecosystem. Dysregulated myeloid or stromal cells, dysfunctional/stressed T cells, chronic wound-healing-like inflammation, and hostile spatial microenvironments can collectively undermine anticancer immunity. Consequently, CD8+T cells may become excluded, anergic, exhausted, metabolically stressed, dysfunctional, or even die. Understanding this diversity and multi-level failure of tumour-associated immune system in human as well as preclinical systems, rather than treating all tumours as simply "T-cell hot vs. cold", is central to our research philosophy. At our CSI Lab, we seek to understand how these disruptions emerge, interact, and evolve, and most importantly, which mechanisms causally drive immunotherapy resistance and can be therapeutically reversed, especially in humans.

Our research combines fundamental cellular and molecular immunology with patient-centred systems immunology, spatial and multi-omics technologies, artificial intelligence (AI), and mechanistic experimentation (Figure 1 & Figure 2). Guided by a reverse translational philosophy, we start with unresolved clinical challenges, decode the complexity of human tumour ecosystems, and use carefully selected experimental models to identify and validate actionable biological mechanisms. This iterative lab-in-the-loop approach continuously connects human observations, data-driven discoveries, and functional validation. Our ultimate ambition is to transform fundamental immunological discoveries into clinically actionable solutions (Figure 2): precision immune biomarkers, next-generation cancer vaccines, myeloid/macrophage-targeting strategies, multispecific antibodies, and rational combination immunotherapies. We particularly focus on hard-to-treat malignancies, including brain, colorectal, and kidney cancers, where existing immunotherapies frequently fail.

Our guiding principle is simple: Understand the complexity > Uncover the causality > Engineer the immunity > Transform patient outcomes. Even if we fail the first time in achieving this, our unique lab-in-the-loop approach allows us to learn from our mistakes and improve our chances of success when we retackle the problem. Thus, our groundbreaking approach starting from human disease and fundamental mechanisms allows us to pave the way for more precise, and personalized cancer immunotherapy (Figure 2).

Figure 2: Our research vision strives to go from human complexity to causally-actionable cancer immunotherapy. The Cell Stress & Immunity (CSI) Lab pursues a patient-centred, reverse-translational research philosophy to understand and overcome cancer immunotherapy resistance. Our approach integrates five interconnected pillars: (1) Clinical challenges arising from refractory tumours, immune heterogeneity, and inadequate biomarkers; (2) Human data ecosystems combining single-cell, spatial and bulk multi-omics with pathology and clinical metadata; (3) Causality-friendly AI and systems medicine to identify mechanistically relevant immune niches, signaling networks, and therapeutic vulnerabilities; (4) Lab-in-the-loop reverse translation to functionally validate discoveries using human-derived experimental systems and disease-relevant mouse models; and (5) Translational outputs, including precision biomarkers, patient stratification, and next-generation immunotherapies. Together, these interconnected approaches aim to transform complex human tumour biology into mechanistic understanding, rational therapeutic innovations, and improved patient outcomes.

Our lab has made several high-impact, pioneering, or ground-breaking discoveries:

A pioneering theoretical framework on the diversity of T cell hypofunction in human cancers.
Exceptional T cell hypofunctional states (tolerized CD8+T cells in glioblastoma paatients, or bystander CD8+T cells in MSS colorectal cancer patients).
AI-driven I-O biomarker, capturing neoantigen-preferring HLA-I repertoire embedded in a spatial macrophage-T cell architecture (kidney cancer patients).
Pan-cancer wound healing-linked TIM3+ VISTA+ CSF1R+ tumoural macrophages.
PD-L1+ macrophages fueling negative feed-forward resistance against anticancer DC vaccines (glioblastoma).
A first-in-class serum-screening myeloid biomarker assay for cancer patients.