KRAS-driven cancers represent one of the largest populations currently addressable with targeted therapies, yet the efficacy of KRAS inhibition differs across tumor types. In non-small cell lung cancer (NSCLC), KRAS inhibitors can induce durable responses and synergize with immune checkpoint blockade. In contrast, microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC), particularly in the metastatic setting, remains largely refractory. The biological basis of this divergence remains poorly
understood.
TITANIC proposes a conceptual shift in the understanding of KRAS-targeted therapy. Rather than viewing KRAS inhibition merely as a strategy to extinguish oncogenic signaling, we hypothesize that KRAS blockade acts as a regulator of tumor-immune ecosystem remodeling. Specifically, we propose that KRAS inhibition differentially rewires innate immune sensing and spatial immune organization, enabling immunotherapy sensitization in NSCLC while failing to overcome immune exclusion in MSS/pMMR CRC
because of defective STING/type I IFN activation, impaired chemokine-driven immune positioning, dysfunctional activation of cytotoxic lymphocytes, and epigenetic stabilization of suppressive immune states.
To address this challenge, TITANIC combines complementary expertise in translational oncology, immunology, epigenetics, computational biology, organoid technologies, and metastatic liver disease. Leveraging patient-derived organoids, immune co-culture systems, advanced transcriptomic and epigenomic profiling, and in vivo models of KRAS-driven lung cancer and colorectal liver metastases, the project focuses on two interconnected immune-organizing systems: the STING/type I IFN pathway and the CCRL2/chemerin-CXCR3 chemokine network. Emerging evidence indicates that these pathways coordinate recruitment, positioning, and activation of NK cells, unconventional T cells, and dendritic cells within tumor tissues. Preliminary consortium data demonstrate that CCRL2 loss promotes IL-17-skewed inflammatory states and accumulation of immunosuppressive neutrophils in KRAS-driven tumors, identifying CCRL2-dependent immune organization as a potential determinant of resistance to immunotherapy.
TITANIC will define how KRAS inhibition and STING activation reshape tumor-intrinsic immune programs and metastatic immune ecosystems, determine the contribution of CCRL2- and CXCR3-dependent immune positioning to therapeutic responsiveness, and establish rational combinatorial strategies integrating KRAS inhibitors, STING agonists, immune checkpoint blockade, and epigenetic modulators.
By integrating mechanistic discovery with translational modeling, TITANIC aims to identify actionable mechanisms and biomarkers of immune resistance, uncover new therapeutic vulnerabilities in immune-cold metastatic CRC, and establish mechanistically informed KRAS/STING-based immunotherapy combinations with broad translational relevance across cancer types.
understood.
TITANIC proposes a conceptual shift in the understanding of KRAS-targeted therapy. Rather than viewing KRAS inhibition merely as a strategy to extinguish oncogenic signaling, we hypothesize that KRAS blockade acts as a regulator of tumor-immune ecosystem remodeling. Specifically, we propose that KRAS inhibition differentially rewires innate immune sensing and spatial immune organization, enabling immunotherapy sensitization in NSCLC while failing to overcome immune exclusion in MSS/pMMR CRC
because of defective STING/type I IFN activation, impaired chemokine-driven immune positioning, dysfunctional activation of cytotoxic lymphocytes, and epigenetic stabilization of suppressive immune states.
To address this challenge, TITANIC combines complementary expertise in translational oncology, immunology, epigenetics, computational biology, organoid technologies, and metastatic liver disease. Leveraging patient-derived organoids, immune co-culture systems, advanced transcriptomic and epigenomic profiling, and in vivo models of KRAS-driven lung cancer and colorectal liver metastases, the project focuses on two interconnected immune-organizing systems: the STING/type I IFN pathway and the CCRL2/chemerin-CXCR3 chemokine network. Emerging evidence indicates that these pathways coordinate recruitment, positioning, and activation of NK cells, unconventional T cells, and dendritic cells within tumor tissues. Preliminary consortium data demonstrate that CCRL2 loss promotes IL-17-skewed inflammatory states and accumulation of immunosuppressive neutrophils in KRAS-driven tumors, identifying CCRL2-dependent immune organization as a potential determinant of resistance to immunotherapy.
TITANIC will define how KRAS inhibition and STING activation reshape tumor-intrinsic immune programs and metastatic immune ecosystems, determine the contribution of CCRL2- and CXCR3-dependent immune positioning to therapeutic responsiveness, and establish rational combinatorial strategies integrating KRAS inhibitors, STING agonists, immune checkpoint blockade, and epigenetic modulators.
By integrating mechanistic discovery with translational modeling, TITANIC aims to identify actionable mechanisms and biomarkers of immune resistance, uncover new therapeutic vulnerabilities in immune-cold metastatic CRC, and establish mechanistically informed KRAS/STING-based immunotherapy combinations with broad translational relevance across cancer types.