RAS signaling and immune cells: a sinister crosstalk in the tumor microenvironment

Table 1 RAS targeted therapy strategies for cancer

Classification	Strategies	Mechanism	Examples	References
Indirectly blocking of RAS signals	Inhibition of RAS membrane localization	Inhibition of farnesylation or PDEδ	Lonafarnib Tipifarnib Salirasib	[10, 83, 84, 86]
	Inhibition of RAS signaling pathway transduction	SHP2 inhibitors	SHP099 TNO155 RMC-4630	[87,88,89]
		SOS1 inhibitors	BAY-293 BI-3406	[90,91,92]
		RAF-MEK-ERK inhibitors	LXH-254 Selumetinib (AZD6244) Tizaterkib (AZD0364)	[93, 94]
		PI3K-AKT-mTOR inhibitors	Alpelisib (BYL719) Lpatasertib Everolimus	[95, 96]
Direct targeting of RAS proteins	Small molecular inhibitors (covalent interactions)	cysteine pocket for KRAS G12C	Sotorasib Adagrasib	[80,81,82]
		arginase pocket for KRAS G12R	α,β-Diketoamide ligand	[97]
		serine pocket for KRAS G12S	β-Lactone ligand	[98]
	Small molecular inhibitors (non-covalent interactions)	Triple complex with KRAS G12D and CypA	RMC9805	[99]
	Small molecular inhibitors (non-covalent interactions)	Salt bridge for KRAS G12D	MRTX-1133 TH-Z835	[100,101,102]
	RAS gene silencing and editing	RNAi CRISPR	siRNAs, shRNAs, CRISPR/Cas9 (DNA), CRISPR/Cas13 (RNA)	[105,106,107,108]
	RAS degraders	PROTAC, linker-based degraders, direct proteolysis degraders	LC-2 KP-14	[109,110,111,112]

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