Table 3.

Summary of detection methods for studying the tumor microenvironment.

Category	Detection method	Techniques	Advantages	Disadvantages	Invasiveness	Sensitivity
Imaging probes	Passive	Enhanced permeability and retention, blood cell membrane coated70–73	Simple, cheap	Non-specific, transient, size, surface charge, and TME dependent	Low	Low
	Targeted	Ligand functionalization, cell-mediated74–83	Significantly enhanced delivery, active internalization	Advanced synthesis, increased clearance rate	Low	Moderate-high
	Sensitized	Pro-drugs, stimuli-responsive systems, and copolymer nanoparticles 84	Enhanced delivery and several stimuli options	Advanced synthesis, stability, and premature drug release	Low	Moderate-high
Non-invasive measurements	Observational	Tumor size and tumor count	Simple and direct	Subjective, bulk measurement, and superficial	Low	Low
		Survival	Simple, population dynamics, and clinically relatable	Larger sample size and slow	Low	Low
	Extracted	Lateral flow assay 85	Rapid, portable, user-friendly, and moderate specificity	Subjective, low signal intensity, batch variability, and limit of detection	Low	Moderate
End-stage assays	Fixed tissue	Histology and immunohistochemistry 86	Simple, relatively inexpensive, and tissue-level detail	Time-consuming preparation and semi-quantitative, subjective	High	Moderate
	Dissociative	Immunoassays, nucleic amplification assays, chromatography, flow cytometry mass spectroscopy, and filter binding assay 87	Standardized technology and signal amplification opportunities	Batch processing, time consuming, technical, and temperature sensitive	High	High
Optical sensors	Fluorescence	Grating coupled-fluorescence plasmonics 88	Stable and multiplexable	Specialized equipment and needs readout standardization	Moderate	High
	Interferometry	Optical backscatter reflectometry 89	Cheap, label free, simple, real time, endoscopy compatible	Long-term stability and temperature dependent	Moderate	High
	Surface plasmon resonance (SPR)	SPR, SPR imaging, localized SPR, and ring resonator90–92	Label free and real time	Complex instrumentation and technical operation	Moderate	High
Electrochemical sensors	Amperometric	Voltammetry and chronoamperometry 93	Simple operation, miniaturization, cheap, real time, and reproducible	Needs redox amplification, temperature sensitive, poor selectivity without membranes or enzymes, and small dynamic range	Moderate	High
	Impedimetric	Conductometry and electrochemical impedance spectroscopy 94	Label free, low cost, simple, real time, stable, low detection limit, wide linear range, and accurate	Low specificity, bulky, low selectivity, and temperature sensitive	Moderate	High
	Potentiometric	Ion-selective electrodes and field-effect transistors 95	Label free, high specificity, real time, inexpensive, and wide detection range	Complex, sensitive to temperature, sensor drift, and pH sensitive	Moderate	High
Gravimetric sensors	Piezoelectric	Quartz crystal microbalance and surface acoustic wave 96	Real time, simple, label free, short analysis, and low cost	Temperature and stress sensitive, poor stability, low repeatability, low liquid sensitivity, and prone to non-specific binding	Moderate	High
	Electromechanical	Cantilever 97	Real time and multiplexable	Temperature sensitive and large readout instrumentation	Moderate	High
	Magnetoelastic	Magnetoelastic ribbon 98	Independent of temperature and pH, wireless, low cost, and stable	Requires external driving and sensing coils	Moderate	High

TME: tumor microenvironment.