MainCancer immunotherapies (ITs) using immune checkpoint blockade (ICB) have transformed treatment for advanced malignancies1,2. Although ICB can elicit durable—sometimes curative—responses in subsets of patients with solid tumours3,4, ~87% do not achieve long-term benefit5. This shortfall reflects tumour mechanisms that evade immune recognition and reduce inherent immunogenicity4. Tumour-associated myeloid cells and their suppressive secretomes are key drivers of limited antitumour immunity, leading to T cell dysfunction and poor outcomes in melanoma6,7,8.Cancer IT strategies aim to deplete, block or reprogramme suppressive immune effectors9. Resistance to anti-CTLA-4 and anti-PD-1/PD-L1 can be mitigated by agonists targeting pattern recognition receptors (PRRs)10, notably Toll-like receptors (TLRs) and the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway11. PRRs may also be activated by endogenous damage-associated molecular patterns (DAMPs)—such as heat-shock proteins (HSPs), adenosine triphosphate (ATP) and calreticulin—generated during cellular stress or death12. PRR engagement promotes co-stimulation, pro-inflammatory gene expression, antigen presentation and phagocytosis9.The STING pathway plays a central role in melanoma and other advanced cancers, mediating innate immunity through cytosolic DNA sensing, senescence induction and type I/II interferon (IFN) production. Pleiotropic cytokines, including interleukin-6 (IL-6), exert pro-tumorigenic effects by upregulating PD-L1, promoting STING degradation and suppressing immunity13. Elevated IL-6 correlates with poor anti-PD-L1 responses14, making the IL-6/PD-L1 axis an attractive therapeutic target. Despite ongoing trials targeting IL-6/PD-1/PD-L1 and/or PRR pathway inhibitors15, no agents have yet been approved.An alternative approach is to tailor physicochemical properties of engineered materials—critical determinants of immune responsiveness16,17. Here we highlight an FDA Investigational New Drug (IND)-cleared, ultrasmall poly(ethylene) glycol (PEG)-coated fluorescent silica nanoparticle, Cornell prime dots (C′ dots), with unexpectedly broad adjuvant-therapeutic activity, now in therapeutic18 and image-guided surgical trials19. Without conjugated agonists or cytotoxic drugs, C′ dots elicit pro-inflammatory and cytotoxic responses in ICB-resistant melanomas localized to the tumor microenvironment. Synthesized in aqueous solution, they exhibit ultrasmall size, controlled surface chemistry and neutral charge20,21,22,23—lacking a protein corona—improving biocompatibility, stability and circulation time24,25. Together with favourable pharmacokinetics (PK)26,27,28 and renal clearance24,29, their efficient tumour penetration and diffusion30,31 leads to high efficacy30,31,32,33,34,35,36 and potent antitumour immunity.Here we exploit these properties to target the novel STING/IL-6/PD-L1 axis in the highly suppressive B16-GMCSF (B16-GM) melanoma model, achieving survival gains beyond traditional IT. C′ dots diminish immune suppression, partly by activating cGAS–STING, triggering immune-related cell death, senescence and cell-cycle arrest, while upregulating PD-L1 and IL-6 on tumour and myeloid cells. This drives tumour immunogenicity, activation of tumour-infiltrating lymphocytes (TILs), macrophage polarization and reduced suppressive immune populations. By contrast, in the less suppressive B16-F10 model, C′ dots primarily induce ferroptosis, an iron-dependent cell death programme. To our knowledge, this is the first study to fully elucidate the adjuvant-therapeutic activity of a clinically validated ultrasmall nanoparticle in combination with IL-6 and PD-L1 blockade to improve treatment outcomes in ICB-resistant models, underscoring the broader potential of ultrasmall particle-based adjuvant therapies to reprogramme the tumour microenvironment (TME) and transform cancer management.Ferroptotic immunomodulation inhibits B16-F10 tumour growthIn previous xenograft studies, systemically administered C′ dots functionalized with alpha melanocyte-stimulating hormone (αMSH) peptides (αMSH-PEG-Cy5-C′ dots/αMSH-C′ dots) induced ferroptosis, tumour regression, iron-related gene upregulation and macrophage recruitment37. To assess ferroptosis- and/or inflammation-driven contributions to TME modulation in immunocompetent settings, we used syngeneic B16-F10 and genetically engineered B16-GM melanoma models, the latter exhibiting greater immune suppression and checkpoint resistance38,39—barriers to effective treatment40. Subcutaneously implanted B16-F10 tumours (150–200 mm3) in C57BL/6 mice received three intravenous (i.v.) doses (12 nmoles per dose every 3 days, Q3D×3) of saline, αMSH-C′ dots (60 μM; 36 nmol; Supplementary Fig. 1a–d) or αMSH-C′ dots + the ferroptosis inhibitor, liproxstatin-1 (liprox)41. Particle treatment reduced tumour volumes by ~65% versus vehicle (Fig. 1a), an effect significantly attenuated by liproxstatin-1, confirming ferroptosis as the principal cytotoxic driver with an added immune-mediated component. Haematoxylin-and-eosin staining showed marked necrosis within αMSH-C′ dot-treated tumours that was abolished by liproxstatin-1, while αMSH-C′ dots + liproxstatin-1 treatment resembled controls (Fig. 1b). Expression of T cell and myeloid cell markers, quantified by immunohistochemistry (IHC) (Supplementary Fig. 2), revealed elevated CD3+, CD8+ T cells and Iba1+ macrophage numbers per unit area over controls post-particle treatment, while CD3+/CD8+ T cells decreased and Iba1+ cells rose with liproxstatin-1 (Fig. 1b,c), suggesting ferroptosis-driven lymphocyte recruitment and macrophage-mediated debris clearance. Combining αMSH-C′ dots with anti-programmed cell death protein 1 (anti-PD-1) antibody yielded near-complete responses, with tumour volumes decreasing ~90% versus 63% for particles alone (Fig. 1d), accompanied by the highest CD3+/CD8+ T cell infiltration per unit area across groups (Fig. 1e). In non-obese diabetic/severe combined immunodeficiency (NOD-SCID; T-/B-cell-deficient) and NOD-SCID gamma (NSG; T-/B-/myeloid-deficient) animals, growth inhibition persisted only in NOD-SCID animals (Fig. 1f,g), indicating that the non-ferroptotic component of efficacy is immune driven and primarily mediated by host myeloid cells.Fig. 1: Ferroptotic cell death, enhanced T cell infiltration and pro-inflammatory changes drive antitumour efficacy and synergize with ICB to inhibit B16-F10 tumour growth in particle-treated mice.a–c, Ferroptosis study: B16-F10 tumour growth inhibition in mice following i.v. injection of αMSH-C′ dots (12 nmol per dose, Q3D×3 (60 μM), red), as against vehicle (blue) and αMSH-C′ dots + liproxstatin (liprox, green) on days 7, 10 and 14 post-implantation (a). Haematoxylin-and-eosin staining of tumour tissue specimens (scale bars, left panel, 1 mm; right panel, 100 μm) (b). Plots of pan T cell (CD3+), helper T cell (CD4+), cytotoxic (CD8+) T cell and macrophage (Iba1+) populations in the TME by IHC (c). d, Tumour growth inhibition in B16-F10 mice injected, as in a ± anti-PD-1 antibody (250 μg, n = 3 doses), using αMSH-C′ dots + anti-PD-1 (green), administered concomitantly, αMSH-C′ dots alone (red), anti-PD-1 alone (grey) or saline vehicle (blue). e, Plots of pan (CD3+), helper (CD4+) and cytotoxic (CD8+) T cell populations. f,g, Tumour growth in particle-treated B16-F10 tumour-bearing NOD-SCID (f) and NSG (g) mice using the regimen in a. Data reflect n = 4 mice per group for all animal studies, mean ± s.e.m. Non-parametric two-way ANOVA with Sidak’s post hoc test was performed for growth inhibition, and one-way ANOVA with Tukey’s test using multiple comparisons was performed for IHC quantification. All statistical tests were two-sided. *P