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. 2022 Jul 4;40(12):1823–1833. doi: 10.1038/s41587-022-01379-y

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a, Schematic of IMDs implanted into a multifocal mouse model of mammary carcinoma (i) showing treatments being released into spatially separated regions of tumors through passive diffusion (ii) and each condition being assayed individually at an angle perpendicular to the device (ii and iii). b, Schematic of the mIHC technique composed of iterative histological stripping, staining and scanning using digital scanning microscopy to detect the target set of markers. c, Acquired images are co-registered with nuclear staining, and the mean intensity of antibody staining within a mask is calculated for each cell to count marker-positive cells in a spatially intact tissue. d, Antibody list primary probe classification used to interrogate a broad range of tumor-intrinsic and TME states. e,f, Multidimensionality reduction in hierarchical gating (e) and list of probe combinations identifying standard cell types (f). g,h, Heat map of mean percentage of positive cells (left) and level of significance (right) at depicted targeted agents and chemotherapies (y axis), with PEG being the negative control (g). Total cell counts were between 3,000 and 5,000 cells per assay area and were matched ±300 total cells for paired samples: experimental versus control region as shown in the macroscopic view of the hematoxylin-stained tumor tissue implanted with IMD (black dashed circle; h). Minimum population proportion within 5% margin of error and 95% confidence level was set to 0.75% (represents 12 cells) to discriminate noise from specific signal. n = 3 wells from three tumors from 2–3 mice per treatment. Significance was calculated by paired sample one-tailed t-test. MMTV-PyMT mice with late-stage spontaneously growing tumors were implanted for 3 days. i–l, Presentation of selected standard cell types in x–y space. [0,0] coordinate is the drug-releasing site; direction of release is upward. Schematics in a,b were partly generated with BioRender. NS, not significant.