Table 1. Factors shown or expected to influence the spreading behavior of CD8⁺ T-cell-secreted cytokines within the TME.

	Cytokine	Observation	References
Mode of secretion	IFNγ	Synaptic release (in vitro)	[24–26]
	TNFα	Multidirectional release (in vitro)	[25]
		TACE-mediated cleavage of transmembrane TNFα (in vitro)	Reviewed in [38]
	IL-2	Synaptic release (in vitro)	[25]
Biochemical stability and proteolytic cleavage	IFNγ	Increased half-life by HS/heparin-mediated prevention of inactivating proteolytic cleavage (in vitro)	[32, 33]
		Activating cleavage up to ten C-terminal amino acids (facilitated by HS/heparin-binding) (in vitro)	[32, 33]
	TNFα	Instable trimers after membrane cleavage (in vitro)	[41]
Receptor-mediated clearance	IFNγ	Receptor expression modulation by internal and environmental factors such as TNFα and IL1β (in vitro)	[27, 28]
	TNFα	TNFR1 and TNFR2 are expressed on distinct cell types and differ in their affinity to TNFα (in vitro/in vivo)	Reviewed in [42]
		TACE-mediated cleavage of TNFRs (in vitro)	[46]
	IL-2	Low, intermediate, and high affinity IL-2 receptor variants, expressed by distinct cell types (in vivo)	Reviewed in [12]
		Receptor expression modulated by FoxP3 and TCR signaling (in vitro)	Reviewed in [12]
		IL-2 spreading distance is influenced by the size of the Treg pool (in vitro, suggestive in vivo)	[51]
		Shedding of the IL-2Rα chain mediated by tumor-cell derived metalloproteinases or as a result of T-cell activation (in vitro)	[53, 54]
Receptor-independent capture	IFNγ	PS-mediated catch and release by tumor cells (in vitro)	[29]
		Galectin-3 mediated containment within the TME (in vivo)	[31]
		HS- or heparin-binding of IFNγ (in vitro)	Reviewed in [33]
		Restricted spreading into tissues following heparin I.V. injection (in vivo)	[34]
	TNFα	Binding to biglycan, decorin, dermatan sulfate, fibronectin and laminin (in vitro)	[43–45]
	Il-2	Binding to galectin-3, collagen and HS/heparin (in vitro)	[31, 56, 57]
Loops	IFNγ	IFNγ-induced IFNγ production in antigen-stimulated CD4+ T cells (in vitro)	[35]
	TNFα	TNFα stimulation increases sTNFR levels (in vitro)	[47]
	Il-2	IL-2 induced expression of IL-2R (in vitro)	[52]
		Inhibition of IL-2 production upon IL-2R signalling (in vitro)	[55]