Assessments of future human survivability under extreme heat with climate change have recently been anchored to a theoretical physiological tipping point: 6 hours of exposure to a wet-bulb temperature (Twet) of 35°C1. This framework broadly treats a fixed Twet as imposing equivalent physiological strain irrespective of the temperature-humidity combinations that produce it. In contrast, human thermoregulation models predict greater physiological strain with increasing ambient temperature under constant Twet conditions2. Here we show that multi-system physiological heat strain differs profoundly in heat-acclimated humans studied under controlled climate-chamber conditions when the canonical 35°C Twet survival limit is imposed across a range of ambient temperatures (38°C with 81% relative humidity (RH), 46°C with 46%RH, 54°C with 26%RH). At 54°C, projected times to heat exhaustion and heat stroke were reduced by ~45% compared with 38°C, driven by an accelerated rise in rectal temperature and accompanied by greater cardiovascular strain and disruption of acid-base balance. These findings demonstrate that the physiological tipping point for human heat tolerance at 35°C Twet is state-dependent, and that utilising a universal Twet survival limit may substantially over-estimate survivability in hot, dry environments projected to expand most rapidly with climate change.