Photothermal therapy (PTT) has garnered significant attention as a noninvasive strategy for cancer treatment, primarily due to its precise spatial and temporal control, minimal invasiveness, and low systemic toxicity relative to traditional modalities such as chemotherapy or radiotherapy [1], [2], [3], [4]. In PTT, organic photothermal agents (PTAs) absorb near-infrared (NIR) light to achieve local hyperthermia for tumor ablation, offering advantages like good biocompatibility and deep tissue penetration [5], [6]. However, conventional PTT effectively kills tumor cells at high temperature (>50 °C), which inevitably causes thermal damage to adjacent normal tissues due to heat diffusion [7], [8]. Furthermore, hyperthermia upregulates heat-shock proteins (HSPs) like HSP90 in cancer cells, activating survival pathways that enhance tumor heat tolerance and suppress antitumor immune responses, increasing risks of recurrence and metastasis [9], [10]. Collectively, these limitations have hindered the widespread clinical application of conventional high-temperature PTT.

To address the limits, mild photothermal therapy (MPTT, temperature ≤ 45 °C) has been proposed, which triggers immunogenic cell death (ICD) through gentle thermal stimulation, thereby minimizing adverse effects on surrounding healthy tissues [11], [12], [13], [14], [15], [16]. Unlike hyperthermia-induced necrosis [17], MPTT induces ICD via “danger signals” molecules [calreticulin (CRT), Adenosine 5’-triphosphate (ATP), high-mobility group box 1 (HMGB1)], activating dendritic cells (DCs), T cells, and promoting the polarization of tumor-associated macrophages to the pro-inflammatory M1 phenotype. This converts “cold” tumors into “hot” immunogenic targets [18], [19], [20], [21], improving immunotherapy efficacy and enabling sustained antitumor effects [22]. The therapeutic model of “thermal stimulation + ICD activation” not only provides localized tumor killing but also has the potential to elicit a systemic antitumor immune response, establishing a theoretical basis for photothermal–immunotherapy synergy [23], [24], [25]. However, tumor cells can rapidly upregulate heat shock proteins (HSP70/90) even under mild heat stress [26], [27], [28], which mitigates thermal damage and confers thermotolerance [29], [30], compromising MPTT effectiveness [31], [32]. This presents a dilemma for MPTT in cancer therapy: superior safety but insufficient effectiveness. Therefore, targeted inhibition of HSP expression has been identified as a key strategy to enhance the effectiveness of MPTT [33], [34]. Studies have attempted to reduce HSP levels using chemical inhibitors or siRNA interference, which has improved tumor cell heat sensitivity to some extent [35], [36], [37]. Among them, HSP90 plays a central role in regulating tumor heat response, apoptosis evasion, and stress recovery [38], [39], [40]. Its inhibition not only reduces thermotolerance but also promotes intracellular accumulation of reactive oxygen species (ROS), intensifies stress responses, and creates favorable conditions for activating other forms of programmed cell death, such as ferroptosis [41], [42], [43], [44].

Against this backdrop, gambogic acid (GA), a natural HSP90 inhibitor, has attracted considerable interest. GA specifically downregulates HSP90 expression, significantly increases tumor cell sensitivity to MPTT, and also induces ferroptosis, thus offering a synergistic killing effect beyond thermal stimulation [45], [46], [47]. Importantly, GA demonstrates good biocompatibility at low doses and shows strong potential for incorporation into multifunctional nanoplatforms in combination with photothermal agents [48], [49], [50].

Building on this foundation, ferroptosis—a non-apoptotic, iron-dependent form of programmed cell death—has emerged as a critical synergistic mechanism in mild photothermal therapy (MPTT)-induced immunogenic cell death (ICD) [51]. Ferroptosis is characterized by glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation, and excessive lipid peroxidation driven by ROS, ultimately leading to membrane disruption [52], [53]. Although mechanistically distinct from classical ICD, growing evidence suggests that ferroptosis can trigger the release of damage-associated molecular patterns (DAMPs), such as CRT exposure and HMGB1 release, consequently promoting DC maturation and boosting antigen presentation [54], [55].

Overall, MPTT, ICD and ferroptosis engage in a mutually reinforcing positive feedback loop. MPTT-induced mild hyperthermia stimulates ICD, accelerates lipid peroxidation and triggers ferroptosis; in turn, ferroptosis amplifies oxidative stress and promotes DAMPs release, further potentiating ICD. Moreover, lipid peroxide (LPO) accumulation has been shown to disrupt heat shock protein stability and function, particularly HSP90, thereby generating an “HSP inhibition–MPTT–LPO” reciprocal amplification cycle, which strengthens photothermal-induced cytotoxicity but also attenuates cellular thermotolerance and augments PTT efficacy [56], [57], [58].

Inspired by aforementioned strategies, we engineered a multifunctional nanoplatform—BQ1-GA nanoparticles (NPs) to circumvent the inherent deficiencies of PTT and amplify the therapeutic efficiency of MPTT via integrated mechanisms including ICD, HSP inhibition and ferroptosis, thus achieving complete tumor eradication in a multifaceted therapeutic approach. Within this synergistic framework (Scheme 1a), GA emerges as a promising dual-functional agent. As a selective HSP90 inhibitor, GA compromises the heat shock response and reduces tumor thermoresistance, sensitizing cells to MPTT [59], [60]. Concurrently, GA promotes GSH depletion and ROS accumulation, effectively inducing ferroptosis [61], [62], [63]. BQ1, an organic NIR photothermal agent with deep tissue penetration (λem 1055 nm) and high photothermal conversion efficiency (PCE: 59.2 %) synthesized in our previous work [64], was co-encapsulated with GA within a DSPE-PEG2000 matrix. As illustrated in Scheme 1b, this platform was designed to orchestrate ICD, HSP inhibition, ferroptosis, apoptosis and mild hyperthermic conditions (≤ 45 °C), thereby enabling comprehensive tumor cell ablation via a multi-pronged therapeutic strategy. The BQ1-to-GA ratio was precisely optimized to balance potent photothermal performance with efficient HSP90 suppression at the lowest possible dose of GA. Upon intravenous administration, BQ1-GA NPs accumulate at tumor sites due to the enhanced permeability and retention (EPR) effect, releasing GA that inhibits HSP90 and disrupts the heat shock response, thus heightening tumor cell sensitivity to thermal stress [65], [66], [67]. Simultaneously, the nanoplatform promotes ROS generation and glutathione depletion, leading to lipid peroxide accumulation, mitochondrial dysfunction, and ferroptosis activation. Under 808 nm laser irradiation (0.5 W/cm2, 10 min), localized mild heating further amplifies ferroptosis and initiates immunogenic cell death (ICD), marked by DAMPs release and DC maturation, forming an MPTT–ICD–ferroptosis, self-amplifying loop. Notably, the ICD cascade also drives tumor-associated macrophage polarization toward the M1 phenotype and enhances antigen presentation, transforming immunologically “cold” tumors into “hot” ones (Scheme 1b). Furthermore, MPTT promotes LPO accumulation, which destabilizes HSP90, thereby creating a self-reinforcing cycle of HSP90–MPTT–LPO. This mechanism further enhances the therapeutic effect of MPTT (Scheme 1b).

Herein, this multipronged nanoplatform orchestrates a synergistic cascade of HSP90 suppression, ferroptosis induction, and ICD activation, offering a promising and clinically translatable strategy for potentiating the efficacy of MPTT in tumor therapy.