Decoding the temporal dimension of innate immunity in intravesical BCG therapy.

Innate immune signals encode functional instructions through temporal patterns such as oscillation frequency and duration-a principle validated at the single-cell level. Yet clinical evaluation of host responses in tumor immunotherapy remains dominated by "how strongly" the immune system is activated, while the waveform of the response-how it unfolds and when it resolves-is largely overlooked. This disconnect raises unresolved questions: why can tumor progression persist despite intense inflammation, and why is fixed-interval maintenance not universally effective? Intravesical BCG instillation offers a way forward: each instillation is a controlled stimulus, voided urine provides a noninvasive sampling window, and oncological plus bladder-function outcomes form a "controlled stimulus-noninvasive sampling-dual-endpoint" closed loop. Using this model, we propose a hypothesis organized around two observation levels. The fundamental unit is the single-instillation single-cytokine waveform-the complete concentration-time curve of one cytokine following one BCG dose; the second is the longitudinal waveform trajectory, which captures how such waveforms evolve across repeated instillations. Both levels reside at a mesoscopic interface between single-cell signaling dynamics and macro-scale clinical outcomes. Our central hypothesis is that temporal features of a single-instillation single-cytokine waveform-time-to-peak, elimination half-life, and decay morphology-carry predictive information independent of peak amplitude. Distinct waveform shapes may differentially instruct adaptive immune quality, while the decay phase defines the time window for immune homeostasis restoration, thus providing a biological rationale for individualized instillation timing. If validated, this framework would expand the evaluation paradigm for intravesical immunotherapy from an "amplitude" dimension to a dual "amplitude + waveform" paradigm.