Second Breath (Preclinical Hypothesis, in silico validated): Biomarker-Guided Local Immune Sequencing for Desmoplastic Tumors

Second Breath is a theoretical/preclinical hypothesis that aims to overcome dominant resistance mechanisms in late-stage solid tumors—especially those unresponsive to immune checkpoint inhibitors (ICIs). Hypothesize that a locally confined, biomarker-guided sequence of enzymatic, inflammatory, and immunologic cues can condition the tumor microenvironment (TME) to permit reinfiltration and activation of anti-tumor immunity. Clinical Problem (Context) Despite ICI success in select cancers, many solid tumors remain “immune-cold,” with: · low T-cell infiltration (exclusion/desert), · a suppressive, dense ECM, · stromal/vascular barriers, · poor responses to systemic immunotherapy. Mechanistic Hypothesis & Proposed Sequence (to be tested preclinically) We hypothesize that local dismantling of physical/biochemical barriers will enable immune reinfiltration. The proposed staged sequence (doses/schedules intentionally omitted pending studies): · Matrix Disruption (local) · Induction of Local Danger Signals Weakly immunogenic bacteria or localized innate agonists to transiently recruit/activate innate cells in situ. · Controlled Cytokine Pulses (local, sequential) Microdosed intratumoral IL-12 → IFN-γ → TNF-α to amplify antigen presentation and effector priming locally. · Autologous T-Cell Augmentation (optional, timing-dependent) Intratumoral/systemic administration of pre-sensitized autologous T cells to exploit the window of heightened local stimulation. · Optional “Cleanup” Phase (safety/containment) Local antibiotics or immunomodulators if needed to cap excessive inflammation and re-establish tissue balance.